1,2,4-tribsubstituted benzenes as inhibitors of 15-lipoxygenase

ABSTRACT

The present invention provides compounds of formula (I) wherein R, Z, Y, W, R 5 , V, and X are as defined in the description, and pharmaceutically acceptable salts thereof, which are useful for the treatment of diseases responsive to the inhibition of the enzyme 15-lipoxygenase. Thus, the compounds of formula (I) and their pharmaceutically acceptable salts are useful for treating diseases with an inflammatory component, including atherosclerosis, diseases involving chemotaxis of monocytes, inflammation, stroke, coronary artery disease, asthma, arthritis, colorectal cancer, and psoriasis.

This application claims the benefit of PCT/US01/14795 filed May 8, 2001,which claims the benefit of U.S. Provisional Application 60/211,498filed Jun. 14, 2000; the entire contents of each of which are herebyincorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides inhibitors of the enzyme 15-lipoxygenase,pharmaceutical compositions comprising said inhibitors, and methods oftreating diseases responsive to inhibition of 15-lipoxygenase.

BACKGROUND OF THE INVENTION

Hypercholesterolemia can induce monocytes to migrate into the arterialwall and mature into foam cells or tissue macrophages that accumulatefatty material, including cholesterol esters. For example, continuedcreation of foam cells thickens the inner lining of medium and largearteries, thereby forming atherosclerotic plaques or lesions containingcholesterol, smooth muscle cells, and connective tissue cells. Affectedarteries lose elasticity and become narrowed or obstructed by theplaques. These events are the hallmark of the disease atherosclerosis.Furthermore, atherosclerotic plaques may collect calcium, becomebrittle, and even rupture, triggering the formation of a blood clot orthrombus capable of occluding an artery and causing a stroke or a heartattack. In addition to atherosclerosis, hypercholesterolemia plays arole in peripheral vascular diseases of small arteries, veins, andlymphatics. Thus, hypercholesterolemia may also affect the arms, legs,kidneys, and other vital organs in addition to the heart and brain.

Cholesterol is transported in blood in particles called lipoproteins,which include low-density lipoproteins (LDL). Lipoproteins also containcholesterol and are necessary for foam cell formation.

Lipoxygenases are enzymes that catalyze the oxidation of polyunsaturatedfatty acids and esters thereof, including those found in low-densitylipoproteins. For example, the enzyme 15-lipoxygenase (15-LO) oxidizesesterified polyenoic fatty acids. 15-LO has been implicated ininflammatory disorders and in the origin and recruitment of foam cells.In addition to modifying lipoproteins involved in the formation of foamcells, 15-LO also mediates an inflammatory reaction in theatherosclerotic lesion In human monocytes, 15-LO is induced by thecytokine IL-4.

Inhibitors of 15-LO are therefore useful to prevent and treat diseaseswith an inflammatory component such as asthma, psoriasis,osteoarthritis, rheumatoid arthritis, colorectal cancer, andatherosclerosis. For example, it has been shown that treatment with aninhibitor of 15-LO suppressed atherogenesis, or the production ofatheroma, a fatty degeneration of the arterial wall, in rabbits fed ahigh-fat diet

A chief object of this invention is to provide new 1,2,4-trisubstitutedbenzenes that are potent inhibitors of 15-LO.

SUMMARY OF THE INVENTION

The invention provides 1,2,4-trisubstituted benzenes, compositions ofmatter containing said benzenes, and methods for treating diseasesrelated to the 15-LO cascade using such compounds or compositions. Theinvention provides compounds of Formula I:

wherein:

-   R is OH, O—C₁-C₄ alkyl, or halo;-   X is R₁, OR₁, SR₁, NHR₁, or NR₁R₂, wherein-   R₁ and R₂ are independenty selected from C₁-C₁₂ alkyl C₂-C₁₂    alkenyl, C₂-C₁₂ alkynyl, benzyl, C₃-C₇ cycloalkyl, C₂-C₆ heteroaryl,    C₂-C₆ heteroalkyl, and phenyl,-   wherein the alkyl alkenyl, alkynyl, heterocyclic radical, benzyl,    and phenyl groups are optionally substituted with from 1 to 5    substituents independently selected from halo, NHR₃, CF₃, C₁-C₆    alkyl, OR₄, CO₂R₃, NO₂, and SR₃,-   wherein R₃ and R₄ are independently H or C₁-C₆ alkyl;-   W and V are independently SO₂ or C═O, provided that when W is SO₂,    —V— can further be a covalent bond and X can further be hydrogen;-   R₅ is H, C₁-C₆ alkyl, or benzyl, wherein benzyl is optionally    substituted with R₁, wherein R₁ is as defined above, or R₅ is a    pharmaceutically acceptable cation;-   Y is NR₆ or O, wherein R₆ is H or C₁-C₆ alkyl;-   Z is 2-indolyl, 3-indolyl, 2-benzimidazolyl, 2-benzoxazolyl,    C(O)N(H)Ph, or N(H)C(O)Ph, which are optionally substituted with    from 1 to 4 substituents independently selected from C₁-C₆ alkyl,    fluoro, chloro, bromo, iodo, nitro, NHR₇, NR₇R₈, and OR₇,-   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl;-   wherein each hydrocarbyl or heterocyclic radical above is optionally    substituted with from 1 to 3 substituents independently selected    from halo, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkenyl, C₁-C₆    alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, N-acetyl,    O-acetyl, C₁-C₆ thioalkyl, C₁-C₆ alkoxy, COOH, COO(C₁-C₆ allyl),    SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl, di(C₁-C₆ alkyl)amino,    and nitro, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, and    phenyl substituents may be optionally substituted with from 1 to 3    substituents independently selected from halo, C₁-C₆ alkyl,    hydroxyl, amino, and nitro; and-   pharmaceutically acceptable salts thereof.

Preferred are compounds of Formula II

and pharmaceutically acceptable salts thereof, wherein X′ is OR₁, SR₁,NHR₁, or NR₁R₂, and R₁, R₂, R, Z, Y, and R₅ are as defined above.

Also preferred are compounds of Formula III

and pharmaceutically acceptable salts thereof, wherein R, Z, Y, and R₅are as defined above.

Preferred are compounds of Formula IV

and pharmaceutically acceptable salts thereof, wherein R₁, R, Z, Y, andR₅ are as defined above.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein R is H or methyl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein R is methyl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is as defined above for Formula I and isoptionally substituted with from 1 to 4 substituents independentlyselected from fluoro, chloro, and methyl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is as defined above for Formula I and issubstituted with from 1 to 3 substituents, wherein the substituents areas defined above for Formula I.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is as defined above for Formula I and issubstituted with from 1 to 3 substituents independently selected fromfluoro, chloro, bromo, and iodo.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is C(O)N(H)Ph.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is C(O)N(H)Ph substituted with at least 1fluoro.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is C(O)N(H)Ph substituted with at least 2fluoro groups.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is C(O)N(O)Ph substituted with at least 2fluoro groups, wherein the said at least 2 fluoro groups are bonded toadjacent carbon atoms.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is (3,4-difluorophenyl)amino-carbonyl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z comprises 2-indolyl optionally substituted withfrom 1 to 4 substituents independently selected from fluoro, chloro, andmethyl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein Z is 5,6-difluoro-indol-2-yl.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein R₅ is H.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein R₅ is a cation selected from an alkali earthmetal cation, an alkaline earth metal cation, ammonium, and choline.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein R₅ is sodium cation, potassium cation, choline,or hemi calcium cation.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein W is SO₂.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein X is R₁, OR₁, SR₁, NHR₁, or NR₁R₂ wherein R₁ andR₂ are independently selected from C₁-C₈ alkyl C₂-C₈ alkenyl, C₂-C₈alkynyl, benzyl, C₃-C₆ cycloalkyl, C₂-C₆ heterocyclic radical, andphenyl, wherein the alkyl, alkenyl, alkynyl, heterocyclic radical,benzyl, and phenyl groups are optionally substituted with from 1 to 3independently selected substituents, wherein the substituents are asdefined above for Formula I.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein X is R₁, OR₁, NHR₁, or NR₁R₂ wherein R₁ and R₂are independently selected from C₂-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅alkynyl, benzyl, and phenyl, wherein the alkyl, alkenyl, alkynyl,benzyl, and phenyl groups are optionally substituted with from 1 to 3independently selected substituents, wherein the substituents are asdefined above for Formula I.

Preferred is a compound of Formula I, and pharmaceutically acceptablesalts thereof, wherein X is phenylamino, phenoxy, alkoxy, alkylamino,dialkylamino, or (carboxy)alkoxy.

Preferred compounds of the present invention are selected from the groupconsisting of:

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,dodecyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-(4-morpholinyl)ethyl ester;

Carbamic acid,[[(5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,3-(dimethylamino) propyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-(1-pyrrolidinyl)ethyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-(dimethylamino)ethyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-phenylethyl ester, monopotassium salt;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-(2-thienyl)ethyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-(ethylsulfonyl)ethyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,3-bromopropyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-[[(phenylmethoxy)carbonyl]amino] ethyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-ethoxyphenyl]amino]-sulfonyl]-,2-(3-thienyl)ethyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,octyl ester;

Carbamic acid,[[[(5-(5,6-difluoro-1H-indol-2-yl)2-methoxyphenyl]-amino]sulfonyl]-methyl-,3-phenylmethoxy)propyl ester;

Carbamic acid,[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-(phenylmethyl)-,3-(phenylmethoxy)propyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-2-(dimethylamino)ethylester, monohydrochloride;

Acetic acid,[[[[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-amino]carbonyl]oxy]-,phenylmethyl ester;

Benzamide,3-[[[[[(3,5-dichlorophenyl)amino]carbonyl]amino]-sulfonyl]-amino]-N-(3,4-difluorophenyl)-4-methoxy-;

Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)-carbonyl]amino]-sulfonyl]amino]-;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,ethyl ester;

Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)-amino]-sulfonyl]amino]carbonyl]amino]-;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,butyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,2-methylpropyl ester;

Carbamic acid,[[(5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,2-methylpropyl ester;

Urea,N-(3,5-dichlorophenyl)-]-N′-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,ethyl ester;

Carbamic acid, [[[5-(1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,ethyl ester;

Urea,N-(4-chlorophenyl)-N′-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-;

Urea,N-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-N′-(4-methylphenyl)-;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-methylester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-heptylester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-pentylester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-(2E)-3-phenyl-2-propenylester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,(2E)-3-phenyl-2-propenyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-2-(1-methylethoxy)ethylester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]-amino]sulfonyl]-,2-(1-methylethoxy)ethyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,phenylmethyl ester,

Sulfamide,N-[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-N′-methyl-;

Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[(methylamino)-sulfonyl]amino]-;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,3-(4-pyridinyl)propyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-2-phenylethylester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,2-phenylethyl ester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,phenylmethyl ester,

Acetic acid,[[[[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl[-amino]carbonyl]oxy]-,methyl ester,

Acetic acid,[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]amino]carbonyl]oxy]-,methyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-3-hydroxypropylester;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,3-hydroxypropyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,2-ethoxyethyl ester,

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-ethoxyethyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-3-(phenylmethoxy)propylester,

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,3-(phenylmethoxy)propyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-hexylester,

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,hexyl ester;

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,1,1-dimethylethyl ester;

Sulfamide, [5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-;

Benzamide, 3-[(aminosulfonyl)amino]-N-(3,4-difluorophenyl)-4-methoxy-;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl ester;

Benzamide,N-(3,4-difluorophenyl)-3-[[[[(dimethylamino)sulfonyl]-amino]carbonyl]-amino]-4-methoxy-;

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,1,1-dimethylethyl ester;

Benzamide,N-(3,4-difluorophenyl)-3-[[[[[[4-(1,1-dimethylethyl)phenyl]-amino]carbonyl]amino]sulfonyl]amino]-4-methoxy-;

Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(3-nitrophenyl)-amino]-carbonyl]amino]sulfonyl]amino]-;

Benzamide,3-[[[[[(3-chlorophenyl)amino]carbonyl]amino]sulfonyl]-amino]-N-(3,4-difluorophenyl)-4-methoxy-;

Benzamide,3-[[[[[[3,5-bis(trifluoromethyl)phenyl]amino]-carbonyl]amino]sulfonyl]-amino]-N-(3,4-difluorophenyl)-4-methoxy-;

Benzamide,3-[[[[[(4-aminophenyl)amino]carbonyl]amino]-sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-,mono(trifluoroacetate);

Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[[3-(trifluoromethyl)phenyl]-amino]carbonyl]-amino]sulfonyl]amino]-;

Benzoic acid,4-[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]-amino]sulfonyl]amino]carbonyl]amino]-;

Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)-amino]-carbonyl]amino]sulfonyl]amino]-;

Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)-carbonyl]-amino]sulfonyl]amino]-;

Benzamide,3-[[[[[(4-chlorophenyl)amino]carbonyl]amino]sulfonyl]-amino]-N-(3,4-difluorophenyl)-4-methoxy-;and

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]methyl-,ethyl ester.

The invention also provides pharmaceutical compositions, comprisingcompounds of Formula I, and pharmaceutically acceptable salts thereof,in admixture with a pharmaceutically acceptable carrier, diluent, orexcipient. Preferred compositions comprise a compound of Formulas IIthrough IV with a pharmaceutically acceptable carrier.

The compounds of Formula I and their pharmaceutically acceptable saltsare useful for treating diseases responsive to inhibition of 15-LO,including atherosclerosis, diseases involving chemotaxis of monocytes,inflammation, stroke, coronary artery disease, asthma, arthritis,including osteoarthritis and rheumatoid arthritis, colorectal cancer,and psoriasis. Thus, the invention also provides methods for treatingmammals with diseases relating to the 15-LO cascade. These methods arefor treating, preventing, or ameliorating the related condition ordisease. These methods include the following.

A method for inhibiting 15-LO, said method comprising administering to apatient in need of 15-lipoxygenase inhibition apharmaceutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

A method for treating or preventing atherosclerosis, said methodcomprising administering to a patient at risk or in need of suchtreatment a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

A method for inhibiting the chemotaxis of monocytes, said methodcomprising administering to a patient in need of inhibition of monocyticmigration a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

A method for treating or preventing inflammation, said method comprisingadministering to patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

A method for treating or preventing stroke, said method comprisingadministering to a patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

A method for treating or preventing coronary artery disease, said methodcomprising administering to a patient at risk or in need of suchtreatment a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

A method for treating or preventing asthma, said method comprisingadministering to patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

A method for treating or preventing arthritis, said method comprisingadministering to patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

A method for treating or preventing colorectal cancer, said methodcomprising administering to a patient at risk or in need of suchtreatment a therapeutically-effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

A method for treating or preventing psoriasis, said method comprisingadministering to a patient at risk or in need of such treatment atherapeutically-effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

Other aspects and features of the invention will be apparent from thedisclosure, examples, and claims set forth below.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds of Formula I, compositions containingthe compounds, methods of making the compounds, and methods of using thecompounds to treat diseases responsive to inhibition of 15-LO. Otherfeatures of the invention, and preferred embodiments thereof, willbecome apparent from the examples and claims below.

A. Terms

Certain terms used herein are defined below and by their usagethroughout this disclosure.

Alkyl groups include aliphatic (i.e., hydrocarbon radicals containinghydrogen and carbon atoms) with a free valence. Alkyl groups areunderstood to include straight chain and branched structures. Preferredalkyl groups have from 1 to 6 carbon atoms. Examples of typical alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, n-butylisobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl,2,3-dimethyl hexyl, 1,1-dimethylpentyl, heptyl, and octyl. Cycloalkylgroups are C₃-C₈ cyclic structures, examples of which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.

Alkyl and cycloalkyl groups can be substituted with 1, 2, 3 or moresubstituents which are independently selected from halo (fluoro, chloro,bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino,cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical,(heterocyclic radical)oxy, (amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₄thioalkyl, C₁-C₄ alkoxy, COOR₆, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂,acetyl, trifluoromethyl, and nitro. Specific examples include COOH,thiomethyl, methoxy, ethoxy, dimethylamino, ethylmethylamino,diethylamino, and chloro. Other examples include fluoromethyl,hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyl,cyclopropylmethyl, methylcyclopropyl, benzyloxyethyl,(3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl,hydroxypropyl, aminocyclohexyl, 2-dimethyl-aminobutyl, methoxymethyl,2-ethoxycyclopentyl, N-pyridinylethyl, diethylaminoethyl, andcyclobutylmethyl.

Alkenyl groups are analogous to alkyl groups, but have at least onedouble-bond (two adjacent sp² carbon atoms). Depending on the placementof a double-bond and substituents, if any, the geometry of thedouble-bond may be entgegen (E), zusammen (Z), cis, or trans. Similarly,alkynyl groups have at least one triple-bond (two adjacent sp carbonatoms). Unsaturated alkenyl or alkenyl groups may have one or moredouble- or triple-bonds, respectively, or a mixture thereof; like alkylgroups, they may be straight chain or branched, and they may besubstituted as described above and throughout the disclosure. Examplesof alkenyls, alkynyls, and substituted forms include cis-2-butenyl,trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl,3-(2′-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl,2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2-propenyl,4hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and2-methyl-2-propenyl.

The foregoing groups are referred to collectively as “hydrocarbyl”groups. More general forms of substituted hydrocarbyls includehydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl,hydroxyaryl, and corresponding forms for the prefixes amino-, halo-(e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-,cycloalkyl- and so on, or combinations of substituents. According toFormula I, therefore, substituted alkyls include hydroxyalkyl,aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such asmethylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl,dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl,(heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl and soon. Where R₁ is phenyl, for example, R₁ thus includes3-halo-4-hydroxyphenyl, 3-(fluoro or chloro)-4-nitrophenyl3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl,3-hydroxy-4-nitrophenyl, 4-hydroxy-3-nitrophenyl, 3-chlorophenyl,4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 2,3-difluorophenyl-2,4-difluorophenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-aminophenyl,4-aminophenyl, 3,5-dimethylphenyl, 3-methylphenyl, 4-methylphenyl,3-nitrophenyl, 4-nitrophenyl, 3-nitro-4-chlorophenyl, 3-cyanophenyl,4-cyanophenyl, 3-methyleneaminophenyl, 4-methyleneaminophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl,4chloro-3-trifluoromethylphenyl, 3-carbomethoxyphenyl,4-carbomethoxyphenyl, bis(3,5-trifluoromethyl)phenyl, 4-t-butylphenyl,4-n-butylphenyl, 4-isopropylphenyl, 3-acetylphenyl, 4-sulfonic acid(e.g., sodium salt), 3-carboxyphenyl, 4carboxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-acetamidophenyl,3-amino-4-halophenyl, 3-alkoxy-4-halophenyl, 3-halo-4-alkylaminophenyl,4-(N,N-dimethylamino)phenyl, 3-cycloalkylphenyl,3(3′,5′-dihalophenyl)-4-nitrophenyl, 4-aryloxyphenyl,arylalkyloxyphenyl, heterocyclic radical phenyl, (heterocyclicradical)oxy, 4-sulfamoylphenyl (or 4-aminosulfonylphenyl),3-(alkylcarbonyloxy)phenyl such as 3-acetylphenyl, and 3-(C₁-C₄thioalkyl)phenyl. It also follow that where Z includes a phenyl, such asZ=NH(CO)Ph, the phenyl can be similarly substituted.

Similarly, the invention features analogous examples of substituted Rwhere R is a heterocyclic radical. Heterocyclic radicals, which includebut are not limited to heteroaryls, include cyclic and bicyclic ringmoieties having between 1 and 4 heteroatoms selected independently fromO, S, and N, and having from 2 to 11 carbon atoms. The rings may bearomatic or nonaromatic, with sp² or sp³ carbon atoms. Examples include:furyl, oxazolyl, isoxazolyl, thienyl, thiophenyl, thiazolyl, pyrrolyl,imidazolyl, triazolyl such as 1,3,4-triazolyl, tetrazolyl, thiazolyl,oxazolyl, xanthenyl, pyronyl, pyridyl, pyrimidyl, triazinyl, pyrazinyl,pyridazinyl, indolyl, and pyrazolyl. Further examples of heterocyclicradicals include piperidyl, quinolyl, isothiazolyl, piperidinyl,morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl,pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, andoctahydrobenzofuranyl. Particularly preferred heterocyclic radicalsinclude 2-pyridyl, 3-pyridyl, 4pyridyl, 3-picolinyl, 2-thienyl,3-thienyl, 2-furyl, 3-furyl, dansyl, 8-quinoyl, 2-acetamido-4-thiazole,and imidazolyl. These may be substituted with one or more substituentssuch as halo, C₁-C₄ alkoxy, COOR₆, SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂,acetyl, trifluoromethyl. Examples of substituted heterocyclic radicalsinclude chloropyranyl, methylthienyl, fluoropyridyl,amino-1-,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.Heterocyclic radicals can be bonded through a carbon atom or aheteroatom.

The term “patient” means a mammal such as a human or a domestic animalsuch as a dog, cat, horse, bovine, porcine, and sheep.

The term “effective amount” means that quantity of a compound of FormulaI that inhibits the 15-LO enzyme in a patient to an extent that resultsin prevention or treatment of an inflammatory condition or otherwisebenefits a patient by virtue of having endogenous 15-LO enzymesinhibited.

The term “halo” includes fluoro, chloro, bromo, and iodo.

The term “amino” means NH₂.

The term “alkylamino” means an alkyl group as defined above bondedthrough an —NH— group.

The term “dialkylamino” means two alkyl groups, each bonded through an—N— group.

The phrase “pharmaceutically acceptable cation” means an alkali oralkaline earth metal cation or a protonated organic amine.

B. Compounds

The invention provides compounds of Formula I and pharmaceuticallyacceptable salts thereof. Also provided are hydrates and solvated formsthereof; masked or protected forms; and racemic mixtures, orenantiomerically or optically pure forms (at least 90%, and preferably95%, 98% or greater purity).

Pharmaceutically acceptable salts include carboxylate salts (e.g., C₁-C₈alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic) and amino acidaddition salts which are within a reasonable benefit/risk ratio,pharmacologically effective, and suitable for contact with the tissuesof patients without undue toxicity, irritation, or allergic response.Representative salts include hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactiobionate, and laurylsulfonate. These may includealkali metal and alkali earth cations such as sodium, potassium,calcium, and magnesium, as well as nontoxic ammonium, quaternaryammonium, and amine cations such as tetramethyl ammonium, methylamine,trimethylamine, and ethylamine. See, for example, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19, which isincorporated herein by reference.

C. Synthesis

The compounds of the present invention can be synthesized according tothe synthetic routes outlined in Schemes 1-4. Scheme 1 illustrates thepreparation of compounds of the present invention of Formula Ia, whichis a compound of Formula I wherein W is SO₂, V is C═O, R₅ is hydrogen, Xis OR₁, SR₁, NHR₁, or NR₁R₂, and R₁, R₂, R, Z, and Y are as definedabove for Formula I. In Scheme 1, chlorosulfonylisocyanate of formula(1) (CSI), is reacted with either an alcohol, thiol, or amine of formulaH—X′, wherein X′ is OR₁, SR₁, or NHR₁ or NR₁R₂, respectively, wherein R₁and R₂ are as defined above, in a nonprotic solvent such as methylenechloride, which can contain, but does not require, an amine such as, forexample, an organic tertiary amine or pyridine, to give achlorosulfonamide of formula (2). The chlorosulfonamide of formula (2)is then further reacted with an alcohol or amine of formula (3) whereinY′ is OH or NH₂, in an organic solvent such as methylene chloride withan amine base such as triethyl amine or pyridine to give a compound ofFormula Ia.

Scheme 2 illustrates the preparation of a compound of the presentinvention of Formula Ib, which is a compound of Formula I wherein W isSO₂, V is C═O, X is OR₁, SR₁, NHR₁, or NR₁R₂, and R₁, R₂, R, Z, Y, andR₅ are as defined above for Formula I. Scheme 2 further illustrates thepreparation of a compound of the present invention of Formula Ic, whichis a compound of Formula I wherein W is SO₂, —V— is a covalent bond, Xis hydrogen, and R, Z, Y, and R₅ are as defined above for Formula I. InScheme 2, a compound of Formula Ia is reacted with an organic base, suchas 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a nonprotic solvent,such as methylene chloride, and alkylated with an alkyl halide offormula R₅-L, wherein L is chloro, bromo, or iodo, to give a compound ofFormula Ib. A compound of Formula Ib, wherein X′ is OR₁, wherein R₁ isan acid labile group such as, for example, tert-butyl or ahydrogenolysis labile group such as benzyl, can further be converted toa compound of Formula Ic by acid-catalyzed cleavage or hydrogenolysis.For example, when R₁ is tert-butyl, the reaction can be carried out bytreating a compound of Formula Ib wherein X′ is OR₁, with hydrogenchloride gas or trifluoroacetic acid (TFA) in a solvent such asmethylene chloride. Alternatively, when R₁ is benzyl, the reaction canbe carried out by treating a compound of Formula Ib wherein X′ is OR₁,with hydrogen gas in the presence of a suitable hydrogenation catalystsuch as palladium (0) tetrakis(triphenyl)-phosphine in a suitablesolvent such as ethanol, tetrahydrofuran (THF), or acetic acid.

Compounds of the present invention of Formula Id, which is a compound ofFormula I wherein —V— is a covalent bond, W is SO₂, X is R₁, and R, Z,Y, and R₅ are as defined above for Formula I, can be synthesizedaccording to the method illustrate in Scheme 3. In Scheme 3, a compoundof formula (3), wherein Y′ is OH or NH₂, is allowed to react with asulfamylchloride of formula (4), wherein R₁ and R₅ are as defined abovefor Formula I, in an organic solvent such as acetonitrile with orwithout an organic base to give a compound of Formula Id.

Amines of formula (3), wherein Y′ is NH₂ in Schemes 1 and 3 can besynthesized according to the methods described in WO 99/32433, which ishereby incorporated by reference. In particular, the procedure ofExample 15 of WO 99/32433 may be used. Additional amines of formula (3),wherein Y′ is NH₂, R is methoxy, and Z is optionally substitutedindol-2-yl wherein the substituents are as defined above for Z inFormula I, can be synthesized according to the method illustrated inScheme 4. In Scheme 4, a phenylacetic acid of formula (5) is convertedto an acid chloride with a chlorinating reagent such as thionyl chlorideor oxalyl chloride, which is then reacted with anisole in the presenceof a Friedel-Crafts catalyst such as aluminum chloride to give a ketoneof formula (6). The ketone of formula (6) is then subjected todinitration using a nitrating reagent such as fuming nitric acid inacetic acid to give a compound of formula (7). The compound of formula(7) is then reduced using a reducing agent such as lithium aluminumhydride or hydrogen and a heavy metal catalyst such as Raney Ni, to givean intermediate di-amine, which undergoes an intermolecular cyclizationto give an amino-indole of formula (8), which is the amine of formula(3) described immediately above wherein R′ is the substituents describedabove for Z of Formula I.

Further guidance and exemplification regarding the synthesis of thecompounds of the present invention is provided in the chemical syntheticExamples 1 through 69 below.

The invention also includes disclosed compounds having one or morefunctional groups (e.g., hydroxyl, amino, or carboxyl) which may bemasked by a protecting group so as to avoid unwanted side reactions.Some of these masked or protected compounds are pharmaceuticallyacceptable; others will be useful as intermediates. The use ofprotecting groups is fully described by Greene and Wuts in “ProtectingGroups in Organic Synthesis” (John Wiley & Sons, 2^(nd) ed.).

Disclosed compounds which are masked or protected may be prodrugs,compounds metabolized or otherwise transformed in vivo to yield adisclosed compound, e.g., transiently during metabolism. Thistransformation may be a hydrolysis or oxidation which results fromcontact with a bodily fluid such as blood, or the action of acids, orliver, gastrointestinal, or other enzymes.

The invention is further described in the working examples describedbelow. The examples are provided for illustration only, and are not tobe construed as limiting the invention in any respect As shown byExamples 1 and 25 described below, compounds of Formulas Ia and Ib maybe prepared by reaction of a penultimate reactive sulfonyl-carbamic acidester derivative such as a chlorosulfonamide of formula (2) or atrialkylamino sulfonyl carbamic acid ester, which is a zwitterioniccompound wherein the chloro of the compound of formula (2) has beenreplaced by a trialkylammonium group and the nitrogen of the carbamicacid ester has been deprotonated. These reactive sulfonyl-carbamic acidester derivatives may optionally be prepared in situ or isolated andpurified before reaction with an amine of formula (3) wherein Y′ is NH₂.

D. EXAMPLES Example 1 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-,Dodecyl Ester

In methylene chloride (40 mL) was stirred chlorosulfonyl isocyanate(CSI) (1.56 g, 11 mmol). To this solution was added dodecanol (1.86 g,10 mmol), in parts. The solution was stirred for 15 minutes. To thissolution was added triethylamine (1.5 g, 15 mmol), and the mixturestirred an additional 15 minutes. To this was added5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (2.33 g, 8.5 mmol),and the mixture stirred at room temperature for 24 hours. The mixturewas washed with water (2×100 mL), and the organic phase dried overmagnesium sulfate. The solvents were evaporated at reduced pressure togive a foam. The foam was dissolved in fresh methylene chloride (40 mL),and the solution was treated with 1N hydrochloric acid (40 mL). Theresulting mixture was vigorously stirred for 20 minutes and thenfiltered to collect the solid. The solid was stirred into acetonitrile(40 mL) and filtered to collect the solid. The solid was then washedwith a mixture of water:acetonitrile (1:1) (10 mL) and dried at 65° C.to give 0.495 g of pure carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-,dodecyl ester. ¹HNMR (DMSO-d₆) δ 0.80-0.84 (t, 3H), 1.14-1.21 (m, 18H),1.4-1.55 (m, 2H), 3.78 (s, 3H), 4.00-4.05 (m, 2H), 6.75 (s, 1H),7.12-7.18 (m, 1H), 7.23-7.31 (m, 1H), 7.41-7.48 (m, 1H), 7.60-7.70 (m,2H), 9.25 (s, 1H), 11.40 (s, 1H), 11.61 (s, 1H) ppm Microanalysis:C₂₈H₃₇F₂N₃O₅S; calculated: C=59.45; H=6.59; N=7.43. found: C=59.46;H=6.81; N=7.32. MS: M⁺+1=566 Da.

Example 2

Carbamic Acid,[[[5[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]-amino]sulfonyl]-,2-(4morpholinyl)ethyl ester

The title compound was synthesized in the same manner as Example 1 using2-morpholinylethanol (1.30 g, 10.0 mmol), CSI (1.56 g, 11.0 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.95 g, 7.0 mmol)to give 0.270 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(4-morpholinyl)ethyl ester. ¹HNMR (DMSO-d₆) δ 2.6-2.75 (m, 4H),2.75-2.85 (m, 2H), 3.55-3.61 (m, 4H), 3.84 (s, 3H), 4.12-4.23 (m, 2H),7.12-7.15 (d, 1H), 7.36-7.44 (m, 1H), 7.50-7.53 (m, 1H), 7.72-7.75 (m,1H), 7.88-7.94 (m, 2H), 8.6-8.8 (br. s, 1H), 10.29 (s, 1H) ppm.Microanalysis: C₂₁H₂₄F₂N₄O₇S.0.22 H₂O; calculated: C=45.51; H=5.17;N=10.11. found: C=45.69; H=5.01; N=10.03. MS: M⁺+1=515.3 Da.

Example 3 Carbamic Acid, [[(5-[[(3,4-diflurophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-(dimethylamino)propyl Ester

The title compound was synthesized in the same manner as Example 1 using2-dimethylaminopropanol (1.03 g, 10.0 mmol), CSI (1.56 g, 11.0 mmol),and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.95 g, 7.0mmol) to give 0.505 g of pure carbamic acid,[[(5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,3-(dimethylamino) propyl ester. ¹HNMR (DMSO-d₆) δ 1.76-1.83 (m, 2H),2.68 (s, 6H), 2.95-2.99 (m, 2H), 3.80-3.83 (m, 2H), 3.85 (s, 3H),7.02-7.05 (d, 1H), 7.36-7.43 (m, 1H), 7.50-7.53 (m, 2H), 7.60-7.70 (br.S, 1H), 7.87-7.93 (m, 1H), 7.99-8.00 (m, 1H), 10.25 (s, 1H) ppm.Microanalysis: C₂₀H₂₄F₂N₄O₆S0.25H₂O; calculated: C=48.92; H=5.03;N=11.41. found: C=48.85; H=4.84; N=11.41. MS: M⁺+1=487.3 Da.

Example 4 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-suffonyl]-,2-(1-pyrrolidinyl)ethyl ester

The title compound was synthesized in the same manner as Example 1 using2-pyrrolidinylethanol (1.15 g, 10.0 mmol), CSI (1.56 g, 11.0 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.95 g, 7.0 mmol)to give 0.305 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,2-(1-pyrrolidinyl)ethyl ester. ¹HNMR (DMSO-d₆) δ 1.79-1.9 (m, 1H),3.11-3.38 (m, 6H), 3.86 (s, 3H), 4.00-4.05 (m, 2H), 7.03-7.05 (d, 1H),7.36-7.43 (m, 1H), 7.50-7.65 (m, 3H), 7.87-7.93 (m, 1H), 8.00 (s, 1H),10.26 (s, 1H) ppm Microanalysis: C₂₁H₂₄F₂N₄O₆S.1.0H₂O; calculated:C=48.83; H=5.07; N=10.85. found: C=49.13; H=4.90; N=10.72. MS:M⁺+1=499.3 Da.

Example 5 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(dimethylamino)ethyl ester

The title compound was synthesied in the same manner as Example 1 using2dimethylaminoethanol (0.89 g, 10.0 mmol), CSI (1.56 g, 11.0 mmol), and3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide (1.95 g, 7.0 mmol) togive 0.499 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(dimethylamino)ethyl ester. ¹HNMR (DMSO-d₆) δ 2.68 (s, 6H), 3.17-3.32(m, 2H), 3.87 (s, 3H), 4.05-4.10 (m, 2H), 7.04-7.06 (d, 1H), 7.36-7.50(m, 1H), 7.52-7.58 (m, 2H), 7.55-7.65 (br. s, 1H), 7.88-7.93 (m, 1H),8.00 (s, 1H), 10.26 (s, 1H) ppm. Microanalysis: C₁₉H₂₂F₂N₄O₆S.0.4H₂O;calculated: C=47.57; H=4.79; N=11.68. found: C=47.75; H=4.62; N=11.51.MS⁺+1=473.3 Da.

Example 6 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-phenylethyl Ester, Monopotassium Salt

To carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-phenylethyl ester (480 mg, 0.949 mmol) in acetonitrile (40 mL) wasadded KOH (1.90 mL of a 0.498N solution) in methanol. The mixture wasstirred at room temperature for 15 minutes and evaporated in vacuo. Theresidue was triturated with ether (25 mL) and filtered to collect thesolid which was dried at 65° C. in vacuo for 3 hours. This gave 0.490 gof the pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-phenylethyl ester, monopotassium salt. ¹HNMR (DMSO-d₆) δ 2.67-2.71 (m,2H), 3.83 (s, 3H), 3.86-3.90 (m, 2H), 6.99-7.02 (d, 1H), 7.10-7.25 (m,5H), 7.35-7.55 (m, 2H), 7.64 (s, 1H), 7.82-7.93 (m, 1H), 8.00 (s, 1H),10.23 (s, 1H) ppm. Microanalysis: C₂₃H₂₀F₂N₄O₆SK. 0.5H₂O; calculated:C=49.99; H=3.83; N=7.60. found: C=49.71; H=3.82; N=7.65. MS: M⁺+1=506.2Da.

Example 7 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(2-thienyl)ethyl ester

The title compound was synthesized in the same manner as Example 1 using2-(2-hydroxyethyl)thiophene (1.28 g, 10.0 mmol), CSI (1.56 g, 11.0mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.95 g,7.0 mmol) to give 0.955 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(2-thienyl)ethyl ester. ¹HNMR (DMSO-6) δ 3.07-3.10 (m, 2H), 3.79 (s,3H), 4.22-4.26 (m, 2H), 6.88-6.92 (m, 2H), 7.16-7.18 (d, 1H), 7.30-7.31(m, 1H), 7.36-7.44 (m, 1H), 7.50-7.53 (m, 1H), 7.85-7.93 (m, 3H), 9.44(s, 1H), 10.32 (s, 1H), 11.50 (s, 1H) ppm. Microanalysis:C₂₁H₁₉F₂N₃O₆S₂.0.1H₂O; calculated: C=49.13; H=3.77; N=8.19; found:C=48.87; H=3.91; N=8.10. MS: M⁺+1=512.2 Da.

Example 8 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(ethylsulfonyl)ethyl ester

The title compound was synthesized in the same manner as Example 1 using2-ethanesulfonyletanol (1.38 g, 10.0 mmol), CSI (1.56 g, 11.0 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.95 g, 7.0 mmol),to give 2.05 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(ethylsulfonyl)ethyl ester. ¹HNMR (DMSO-d₆) δ 1.13-1.17 (m, 3H),3.08-3.13 (m, 2H), 3.40-3.50 (m, 2H), 3.84 (s, 3H), 4.38-4.41 (m, 2H),7.19-7.21 (d, 1H), 7.37-7.51 (m, 2H), 7.89-7.94 (m, 3H), 9.60 (s, 1H),10.33 (s, 1H), 11.59 (s, 1H) ppm. Microanalysis: C₁₉H₂₁F₂N₃O₈S₂.0.15H₂O;calculated: C=43.53; H=4.10; N=8.02; found: C=43.50; H=4.09; N=8.01. MS:M⁺+1=522.2 Da.

Example 9 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-bromopropyl ester

The title compound was synthesized in the same manner as Example 1 using3-bromopropanol (1.39 g, 10.0 mmol), CSI (1.56 g, 11.0 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.95 g, 7.0 mmol)to give 0.495 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-bromopropyl ester. ¹HNMR (DMSO-d₆) δ 2.06-2.13 (m, 2H), 3.51-3.54 (m,2H), 3.84 (s, 3H), 4.14-4.17 (m, 2H), 7.18-7.21 (d, 1H), 7.37-7.53 (m,2H), 7.86-7.94 (m, 3H), 9.53 (s, 1H), 10.32 (s, 1H), 11.40 (s, 1H) ppm.Microanalysis: C₁₈H₁₈F₂BrN₃O₆S; calculated: C=41.39; H=3.47; N=8.04.found: C=41.60; H=3.44; N=7.99. MS: M⁺+1=524.2 Da.

Example 10 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-[[(phenylmethoxy)carbonyl]amino]ethyl ester

The title compound was synthesized in the same manner as Example 1 using(2-hydroxyethyl)carbamic acid benzylester (1.95 g, 10.0 mmol), CSI (1.56g, 11.0 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide(1.95 g, 7.0 mmol) to give 0.639 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-[[(phenylmethoxy)carbonyl]amino]ethyl ester. ¹HNMR (DMSO-d₆) δ3.26-3.33 (m, 2H), 3.81 (s, 3H), 4.07-4.09 (m, 2H), 4.98 (s, 2H),7.16-7.18 (d, 1H), 7.28-7.44 (m, 7H), 7.50-7.53 (m, 1H), 7.86-7.94 (m,3H), 9.45 (s, 1H), 10.32 (s, 1H), 11.40 (s, 1H) ppm. Microanalysis:C₂₅H₂₄F₂N₄O₈S. _(0.2)H₂O; calculated: C=51.53; H=4.22; N=9.62. found:C=51.15; H=4.08; N=9.51. MS: M⁺+1=579.3 Da.

Example 11 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(3-thienyl)ethyl ester

The title compound was synthesized in the same manner as Example 1 using3-(2-hydroxyethyl)thiophene (1.28 g, 10.0 mmol), CSI (1.56 g, 11.0mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.95 g,7.0 mmol) to give 0.360 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(3-thienyl)ethyl ester. ¹HNMR (DMSO-d₆) δ 2.87-2.91 (m, 2H), 3.80 (s,3H), 4.22-4.25 (m, 2H), 7.01-7.02 (d, 1H), 7.17-7.20 (m, 2H), 7.37-7.44(m, 2H), 7.51-7.57 (m, 1H), 7.87-7.95 (m, 3H), 9.45 (s, 1H), 10.33 (s,1H), 11.46 (s, 1H) ppm. Microanalysis: C₂₁H₁₉F₂N₃O₆S₂; calculated:C=49.31; H=3.74; N=8.21. found: C=48.91; H=3.76; N=8.09. MS: M⁺+1=512.2Da.

Example 12 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-octylester

The title compound was synthesized in the same manner as Example 1 usingn-octanol (1.30 g, 10.0 mmol), CSI (1.56 g, 11.0 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (2.33 g, 8.5 mmol)to give 0.935 g of pure carbamic acid,[[[5-(5,6-difluoro-1-H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-octylester. ¹HNMR (DMSO-d₆) δ 0.77-0.81 (m, 3H), 1.14-1.25 (m, 10H),1.47-1.55 (m, 2H), 3.78 (s, 3H), 4.00-4.04 (m, 2H), 6.72 (s, 1H),7.12-7.14 (d, 1H), 7.25-7.30 (m, 1H), 7.74-7.46 (m, 1H), 7.61-7.67 (m,2H), 9.27 (s, 1H), 11.38 (s, 1H), 11.62 (s, 1H) ppm. Microanalysis:C₂₄H₂₉F₂N₃O₅S; calculated: C=56.57; H=5.74; N=8.25. found: C=56.17;H=5.56; N=8.22. MS: M⁺+1=510.3 Da.

Example 13 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]methyl-,3(phenylmethoxy)propyl ester

To carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-3-(phenylmethoxy)propylester (0.70 g, 1.28 mmol) in THF (12 mL) was added sequentially, DBU(0.198 g, 1.3 mmol), and then methyl iodide (0.185 g, 1.3 mmol). Themixture stirred overnight at room temperature. The solution was dilutedwith methylene chloride (75 mL) and washed with water (75 mL). Theorganic phase dried over magnesium sulfate and then evaporated in vacuoto give the crude compound. This was purified by flash chromatographyover silica gel (9:1, methylene chloride:ethyl acetate). The appropriatefactions were combined and evaporated in vacuo to give 0.380 g of purecarbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]methyl-,3-(phenylmethoxy)propyl ester. ¹HNMR (DMSO-d₆) δ 1.78-1.87 (m, 2H), 2.97(s, 3H), 3.38-3.48 (m, 2H), 3.76 (s, 3H), 4.15-4.18 (m, 2H), 4.36 (s,2H), 6.75 (s, 1H), 7.12-7.14 (d, 1H), 7.20-7.35 (m, 6H), 7.42-7.47 (m,1H), 7.68-7.75 (m, 2H), 9.69 (s, 1H), 11.67 (s, 1H) ppm. Microanalysis:C₂₇H₂₇F₂N₃O₆S; calculated: C=57.95; H=4.86; N=7.53. found: C=57.99;H=4.94; N=7.33. MS: M⁺+1=560.3 Da.

Example 14 Carbamic Acid,[[(5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-(phenylmethyl),3-(phenylmethoxy)propyl ester

The title compound was synthesized in the same manner as Example 13using carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-3-(phenylmethoxy)propylester (0.640 g, 1.17 mmol), benzyl bromide (0.205 g, 1.2 mmol), and DBU(0.183 g, 1.2 mmol) to give 0.215 g of pure carbamic acid,[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]phenylmethyl)-,3-(phenylmethoxy)propyl ester. ¹HNMR (DMSO-d₆) δ 1.81-1.85 (m, 2H),3.35-3.39 (m, 2H), 3.71 (s, 3H), 4.19-4.22 (m, 2H), 4.33 (s, 2H), 4.60(s, 2H), 6.74 (s, 1H), 7.06-7.33 (m, 12H), 7.42-7.47 (m, 1H), 7.67-7.71(m, 2H), 9.75 (s, 1H), 11.66 (s, 1H) ppm. Microanalysis: C₃₃H₃₁F₂N₃O₆S;calculated: C=62.35; H=4.92; N=6.61. found: C=62.26; H=5.00; N=6.27. MS:M⁺+1=636.3 Da.

Example 15 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-2-(dimethylamino)ethylester, Monohydrochloride

The title compound was synthesized in the same manner as Example 1 using2-dimethylaminoethanol (0.802 g, 9.0 mmol), CSI (1.27 g, 9.0 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.91 g, 7.0 mmol)to give 0.395 g of pure carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-2-(dimethylamino)ethylester, monohydrochloride. ¹HNMR DMSO-d₆) δ 2.71 (s, 6H), 3.20-3.40 (m,2H), 3.80 (s, 3H), 420-4.35 (br. s, 2H), 6.66 (s, 1H), 7.08-7.10 (d,1H), 7.26-7.30 (m, 1H), 7.44-7.52 (m, 2H), 7.77 (s, 1H), 11.63 (s, 1H)ppm. Microanalysis: C₂₀H₂₂F₂N₄O₅S.0.25HCl.0.25 H₂O; calculated: C=48.45;H=4.78; N=11.30. found: C=48.30; H=4.65; N=11.08. MS: M⁺+1=469.3 Da.

Example 16 Acetic Acid,[[[[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]amino]carbonyl]oxy]-,phenylmethyl ester

The title compound was synthesized in the same manner as Example 1 usingbenzyl-2-hydroxyacetate (1.50 g, 9.0 mmol), CSI (1.27 g, 9.0 mmol), and5(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.91 g, 7.0 mmol)to give 1.2 g of pure acetic acid,[[[[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]amino]carbonyl]oxy]-,phenylmethyl ester. ¹HNMR (DMSO-d₆) δ 3.75 (s, 3H), 4.77 (s, 2H), 5.16(s, 2H), 6.76 (s, 1H), 7.12-7.14 (m, 1H), 7.26-7.33 (m, 6H), 7.42-7.47(m, 1H), 7.64-7.7 (m, 2H), 9.51 (s, 1H), 11.61 (s, 1H), 11.77 (s, 1H)ppm. Microanalysis: C₂₅H₂₁F₂N₃O₇S; calculated: C=55.04; H=3.88; N=7.70.found: C=54.73; H=3.82; N=7.55. MS: M⁺+1=546.2 Da.

Example 17 Benzamide,3-[[[[[(3,5-dichlorophenyl)amino]-carbonyl]amino]sulfonyl]-amino]-N-(3,4-difluorophenyl)-4-methoxy

The title compound was synthesized in the same manner as Example 1 using3,5-dichloroaniline (1.0 g, 6.2 mmol), CSI (0.64 mL, 4.4 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.24 g, 7.0 mmol)to give 0.05 g of pure benzamide,3-[[[[[(3,5-dichlorophenyl)amino]-carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-.Microanalysis: C₂₁H₁₆Cl₂F₂N₄O₅S; calculated: C=46.25; H=2.96; N=10.27;found: C=46.30; H=3.32; N=9.93. MS: M⁺+1=544.9 Da.

Example 18 Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)carbonyl]-amino]sulfonyl]amino]

The title compound was synthesized in the same manner as Example 1 usinganiline (0.59 g, 6.4 mmol), CSI (0.67 mL, 7.7 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.19 g, 4.3 mmol)to give 0.17 g of pure benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)carbonyl]amino]sulfonyl]amino]-.Microanalysis: C₂₁H₁₈F₂N₄O₅S; calculated: C=52.94; H=3.81; N=11.76.found: C=52.70; H=4.04; N=11.51. MS: M⁺+1=477 Da.

Example 19 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,Ethyl Ester

The title compound was synthesized in the same manner as Example 1 usingethanol (0.52 g, 11.3 mmol), CSI (1.08 mL, 12.4 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.1 g, 4.0 mmol) togive 0.65 g of pure carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,ethyl ester. Microanalysis: C₁₇H₁₇F₂N₃O₆S; calculated: C=47.55; H=3.99;N=9.79. found: C=47.66; H=3.88; N=9.42. MS: M⁺+1=430 Da.

Example 20 Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)-amino]sulfonyl]amino]carbonyl]amino]

3-Amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (3.0 g, 10.8 mmol)was dissolved in 200 mL dichloromethane and added dropwise to a solutionof CSI (1.15 mL, 12.9 mmol) in 50 mL of dichloromethane at 0° C. Theresulting white suspension was stirred for 1 hour and then filtered togive 2.94 g of a chlorosulfonyl urea intermediate. This intermediate(1.4 g, 3.5 mmol) was added in portions to a solution of p-anisidine(0.43 g, 3.5 mmol) in 50 mL acetone with triethylamine (1.94 mL, 13.9mmol). The resulting mixture was stirred for 16 hours at roomtemperature. The reaction mixture was concentrated in vacuo, and theresidue was partitioned between ethyl acetate and 1 M HCl. The ethylacetate layer was dried over magnesium sulfate, filtered, andconcentrated to give a pale pink oily solid. Recrystallization fromdichloromethane gave 0.55 g of pure benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)amino]-sulfonyl]amino]carbonyl]amino]-.Microanalysis: C₂₂H₂₀F₂N₄O₆S; calculated: C=52.17; H=3.98; N=11.06.found: C=52.20; H=4.06; N=10.98. MS: M⁺+1=507 Da.

Example 21 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-,Butyl Ester

To a cold solution of chlorosulfonylisocyanate (3.1 g, 0.022 mol) indichloromethane (20 mL) was added dropwise a solution of n-butanol (1.5g, 0.020 mol) in dichloromethane (5 mL). The solution gradually warmedto room temperature and was stirred overnight. The solvent wasconcentrated in vacuo leaving a viscous liquid. The crude product wastriturated with hexane/ethyl acetate (4:1) and concentrated to give thesulfamoyl chloride intermediate as a white solid. The solid wassuspended in hexane and collected by filtration. Yield: 3.4 g, (87%) ofchlorosulfonyl-carbamic acid, n-butyl ester, which was used withoutfurther characterization.

A solution of the chlorosulfonyl carbamic acid, n-butyl ester (3.4 g,0.018 mol) in benzene (25 mL) was added dropwise at room temperature toa stirred solution of triethylamine (4.5 g, 0.044 mol) in benzene (25mL). The reaction mixture was stirred overnight, filtered, and thefiltrate was concentrated in vacuo to give a viscous liquid. A portionof the liquid obtained (0.5 g, 1.78 mmol) was diluted with benzene (50mL) and treated with5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.48 g, 1.78 mmol)in one portion. The reaction mixture was stirred at room temperatureovernight, at which time it was diluted with aqueous HCl (25 mL) andethyl acetate (50 mL). The organic phase was separated and washed withbrine, dried (MgSO₄), and concentrated. The resulting residue wasrecrystallization from hexane/ethyl acetate to give 0.12 g (15%) ofcarbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl)-amino]sulfonyl]-,butyl ester. Mp 193-194° C.; ¹HNMR (CDCl₃/DMSO-d₆) δ 11.1 (s, 1H), 9.3((s, 1H), 7.9 (s, 1H), 7.7-7.6 (m, 3H), 7.3 (m, 1H), 7.1 (m, 1H), 6.9(d, 1H), 3.9 (s, 3H), 3.8 (d, 2H), 1.8 (m, 1H), 0.8 (m, 6H) ppm.Microanalysis: C₁₉H₂₂F₂N₃O₆S; calculated: C=49.78; H=4.84; N=9.17.found: C=49.88; H=4.53; N=9.16. MS:M⁺+1=457 Da.

Example 22 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-,2-methylpropyl ester

The title compound was synthesized in the same manner as Example 1 usingisobutanol (1.5 g 0.020 mol) to give 0.15 g (18%) of pure carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,2-methylpropyl ester, which was isolated as a cream colored solid. Mp187-189° C.; ¹HNMR (CDCl₃/DMSO-d₆) δ 11.0 (s, 1H), 10.4 (s, 1H), 7.7 (s,1H), 7.6 (s, 1H), 7.4 (d, 1H), 7.3 (m, 1H), 7.1, (m, 1H), 6.9 (d, 1H),6.6 (s, 1H), 3.8 (s, 3H), 3.78 (d, 2H), 1.8, (m, 1H), 0.7 (d, 6H) ppm.Microanalysis: C₂₀H₂₁F₂N₃O₅S; calculated: C=52.97; H=4.67; N=9.27.found: C=52.64; H=4.57; N=9.10. MS: M⁺+1=453 Da.

Example 23 Carbamic Acid,[[(5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-methylpropyl ester

The title compound was prepared by replacing5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine with3-amino-N-(2,4-difluorophenyl)-4-methoxy-benzamide (0.49 g, 1.78 mmol)in the procedure used in Example 22 to give 0.17 g (21%) of purecarbamic acid,[[(5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-methylpropyl ester as a white powder. Mp 188-190° C.; ¹HNMR(CDCl₃/DMSO-d₆) δ 10.9 (s, 1H), 10.3 (s, 1H), 7.7 (s, 1H), 7.6 (s, 1H),7.4 (d, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 6.9 (d, 1H), 6.6 (s, 1H), 4.1 (t,2H), 3.9 (s, 3H), 1.5 (m, 2H), 1.2 (m, 2H), 0.8 (t, 3H) ppm.Microanalysis: C₂₀H₂₁F₂N₃O₅S.0.38H₂O; calculated: C=52.19; H=4.76;N=9.13. found: C=52.18; H=4.80; N=8.96. MS: M⁺+1=457 Da.

Example 24 Urea,N-(3,5-dichlorophenyl)-]-N′-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]

Urea,N-(3,5-dichlorophenyl)-]-N′-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]was synthesized in the same manner as Example 1 using3,5-dichloroaniline (2.0 g, 12.3 mmol), CSI (1.28 mL, 14.8 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.3 mmol);Microanalysis: C₂₂H₁₆Cl₂F₂N₄O₄S.2.0H₂O; calculated: C=45.77; H=3.49;N=9.70. found: C=45.79; H=3.08; N=9.68. MS: M⁺=541 Da.

Example 25 Carbamic Acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-,ethyl ester

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,ethyl ester was synthesized in the same manner as Example 1 using5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.5 g, 1.8 mmol)and Et₃NSO₂NCO₂Et (0.46 g, 1.8 mmol); Microanalysis:C₁₈H₁₇F₂N₃O₅S.C₄H₈O₂; calculated: C=51.46; H=4.91; N=8.18; found:C=51.86; H=4.57; N=8.58. MS: M⁺+1=426.1 Da.

Example 26 Carbamic Acid,[[[5-(IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-, Ethyl Ester

Carbamic acid, [[[5-(IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,ethyl ester was synthesized in the same manner as Example 1 using5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.87 g, 3.64 mmol) andEt₃NSO₂NCO₂Et (0.92 g, 3.64 mmol); Microanalysis: C₁₈H₁₉N₃O₅S;calculated: C=55.52; H=4.92; N=10.79. found: C=55.30; H=5.04; N=10.39.MS: M⁺+1=390.1 Da.

Example 27 Urea, N-(4-chlorphenyl)-N′-[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]

Urea,N-(4-chlorophenyl)-N′-[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]was synthesized in the same manner as Example 1 using5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.41 g, 1.5 mmol)and (4-chlorophenyl)NHCONHSO₂Cl (0.4 g, 1.5 mmol); Microanalysis:C₂₂H₁₇Cl₂F₂N₄O₄S.0.5 H₂O; calculated: C=52.19; H=4.76; N=9.13. found:C=52.18; H=4.80; N=8.96. MS: M⁺+1=507 Da.

Example 28 Urea,N-[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-N′-(4-methylphenyl)

Urea,N-[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-N′-(4-methylphenyl)was synthesized in the same manner as Example 1 using5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.33 g, 1.2 mmol)and (4-methylphenyl)NHCONHSO₂Cl (0.3 g, 1.2 mmol); Microanalysis:C₂₃H₂₀F₂N₄O₄S.1.75 H₂O; calculated: C=53.33; H=4.57; N=10.82. found:C=53.41; H=4.16; N=10.42. MS: M⁺+1=487 Da.

Example 29 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-methylester

Carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-methylester was synthesized in the same manner as Example 1 using5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine and Et₃NSO₂NCO₂Me;Microanalysis: C₂₀H₂₁F₂N₃O₅S.0.38 H₂O; calculated: C=52.19; H=4.76;N=9.13. found: C=52.18; H=4.80; N=8.96. MS: M⁺+1=457 Da.

Example 30 Carbamic Acid,[[[5-(5,6-difluoro-IH-indo-2-yl)2-methoxyphenyl]amino]-sulfonyl]-heptylester

The title compound was synthesized as in Example 1 using heptyl alcohol(1.3 mL, 8.9 mmol), CSI (0.85 mL, 9.8 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (2.4 g, 8.9 mmol)to give 2.9 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-heptylester. Microanalysis: C₂₃H₂₇F₂N₃O₅S; calculated: C=55.75; H=5.49;N=8.48; found: C=55.64; H=5.61; N=8.41. MS: M⁺+1=496 Da. Mp 178-180° C.¹HNMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 11.38 (s, 1H), 9.27 (s, 1H),7.67 (d, J=1.9 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.49-7.44 (m, 1H),7.30-7.26 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.72 (s, 1H), 4.02 (t, J=6.5Hz, 2H), 3.78 (s, 3H), 1.17-1.13 (m, 10H), 0.78 (t, J=6.5 Hz, 3H).

Example 31 Carbamic Acid,[[[5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-pentylester

The title compound was synthesized as in Example 1 using pentyl alcohol(0.97 mL, 8.9 mmol), CSI (0.85 mL, 9.8 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (2.4 g, 8.9 mmol),to give 2.9 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl)-pentylester. Microanalysis: C₂₁H₂₃F₂N₃O₅S; calculated: C=53.95; H=4.96;N=8.99; found: C=53.86; H=5.06; N=8.95. MS: M⁺+1=468 Da. Mp 182-184° C.¹HNMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 11.38 (s, 1H), 9.27 (s, 1H),7.68 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.49-7.44 (m, 1H), 7.30-7.26 (m,1H), 7.14 (d, J=8.7 Hz, 1H), 6.72 (s, 1H), 4.03 (t, J=6.8 Hz, 2H), 3.78(s, 3H), 1.20-1.13 (m, 6H), 0.78 (t, J=6.5 Hz, 3H).

Example 32 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-(2E)-3-phenyl-2-propenylester

The title compound was synthesized as in Example 1 using cinnamylalcohol (0.99 g, 7.3 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.51 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-(2E)-3-phenyl-2-propenylester. Microanalysis: C₂₅H₂₁F₂N₃O₅S; calculated: C=58.47; H=4.12;N=8.18. found: C=58.59; H=4.09; N=8.20. MS: M⁺+1=514 Da. Mp 149-152° C.¹HNMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 11.51 (s, 1H), 9.44 (s, 1H),7.71 (s, 1H), 7.66-7.64 (m, 1H), 7.46-7.13 (m, 8H), 6.75-6.65 (m, 2H),6.37-6.30 (m, 1H), 4.77 (d, J=6.1 Hz, 2H), 3.78 (s, 3H).

Example 33 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,(2E)-3-phenyl-2-propenyl ester

The title compound was synthesized as in Example 1 using cinnamylalcohol (0.99 g, 7.3 mmol), CSI (0.42 mL, 4.9 mmol), and3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide (1.0 g, 3.6 mmol) togive 0.55 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,(2E)-3-phenyl-2-propenyl ester. Microanalysis: C₂₄H₂₁F₂N₃O₆S.0.18C₆H₁₆NCl; calculated: C=55.55; H=4.44; N=8.21; found: C=55.32; H=4.16;N=8.30. MS: M⁺−1=516 Da. Mp 159-163° C. ¹HMR (400 MHz, DMSO) δ 11.49 (s,1H), 10.34 (s, 1H), 9.53 (s, 1H), 7.93-7.87 (m, 3H), 7.54-7.16 (m, 8H),6.70-6.66 (m, 1H), 6.38-6.31 (m, 1H), 4.76-4.75 (d, J=5.8 Hz, 2H), 3.82(s, 3H).

Example 34 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-2(1-methylethoxy)ethylEster

The title compound was synthesized as in Example 1 using2-isopropoxyethanol (0.47 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.67 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-2-(1-methylethoxy)ethylester. Microanalysis: C₂₁H₂₃F₂N₃O₆S.0.3 C₆H₁₆NCl.0.41H₂O; calculated:C=51.46; H=5.42; N=8.69. found: C=51.45; H=5.18; N=8.85. MS: M⁺+1=484Da. Mp 158-163° C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.64 (s, 1H), 11.53 (s,1H), 9.27 (s, 1H), 7.71 (s,1H), 7.62 (d, J=7.7 Hz, 1H), 7.50-7.46 (m,1H), 7.32-7.28 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 4.13 (s,2H), 3.80 (s, 3H), 3.52-3.47 (m, 3H), 1.00 (d, J=6.0 Hz, 6H).

Example 35 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(1-methylethoxy)ethyl ester

The title compound was synthesized as in Example 1 using2-isopropoxyethanol (0.47 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.0 g, 3.6 mmol) togive 0.76 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(1-methylethoxy)ethyl ester. Microanalysis: C₂₀H₂₃F₂N₃O₇S; calculated:C=49.28; H=4.76; N=8.62; found: C=49.08; H=4.66; N=8.43. MS: M⁺+1=488Da. ¹HNMR (400 M DMSO-d₆)δ 11.50 (s, 1H), 10.33 (s, 1H), 9.42 (s, 1H),7.95-7.86 (m, 3H), 7.54-7.52 (m, 1H), 7.45-7.38 (m, 1H), 7.19 (d, J=8.7Hz, 1H), 4.16-4.14 (m, 2H), 3.84 (s, 3H), 3.56-3.50 (m, 3H), 1.03 (d,J=6.0 Hz, 6H).

Example 36 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-methoxyphenyl]amino]-sulfonyl]-,Phenylmethyl ester

The title compound was synthesized as in Example 1 using benzyl alcohol(0.44 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.56 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,phenylmethyl ester. Microanalysis: C₂₃H₁₉F₂N₃O₅S; calculated: C=56.67;H=3.93; N=8.62. found: C=56.29; H=3.76; N=8.41. MS: M⁺+1=488 Da. Mp177-180° C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 11.54 (s, 1H),9.41 (s, 1H), 7.70 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.49-7.44 (m, 1H),7.32-7.27 (m, 6H), 7.14 (d, J=8.4 Hz, 1H), 6.72 (s, 1H), 5.15 (s, 2H),3.73 (s, 3H).

Example 37 Sulfamide,N-[5-(5,6-diflouo-IH-indo-2-yl)-2-methoxyphenyl]-N′-methyl

Methyl sulfamic acid (2.0 g, 18.0 mmol) was suspended in benzene, andphosphorous pentachloride (3.7 g, 18.0 mmol) was added The mixture wasrefluxed for 3 hours. The supernatant was decanted into a separateflask, leaving any solid behind. The benzene was removed bydistillation, and the remaining oil, methyl sulfamyl chloride, wasstored under nitrogen. Methyl sulfamyl chloride (0.80 g, 6.2 mmol) wasdissolved in 50 mL of methylene chloride, and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)and triethylamine (1.0 mL, 7.2 mmol) were added. The solution wasstirred overnight The resulting mixture was washed with water (2×50 mL),and the organic phase was dried over magnesium sulfate. The solventswere evaporated under reduced pressure to give a foam. The foam wasredissolved in a small amount of fresh methylene chloride and treatedwith 1N hydrochloric acid. (20 mL). Vigorous shaking produced aprecipitate, which was collected via filtration. The resulting powderwas triturated sequentially with water, methylene chloride, and ether.The triturated solid was dried under vacuum to give 0.26 g of sulfamide,N-[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]-N′-methyl-.Microanalysis: C₁₅H₁₅F₂N₃O₄S.0.15 CH₂Cl₂.0.08 C₆H₁₆NCl; calculated:C=51.07; H=4.27; N=11.03. found: C=51.13; H=4.26; N=10.83. MS: M⁺+1=368Da. Mp 196-200° C. ¹HNMR (400 Mz, DMSO-d₆) δ 11.59 (s, 1H), 8.55 (s,1H), 7.70 (s,1H), 7.55-7.45 (m, 1H), 7.32-7.28 (m, 1H), 7.18 (d, J=4.3Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 6.73 (s, 1H), 3.84 (s, 3H), 2.53 (s,3H).

Example 38 Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[(methylamino)-sulfonyl]amino]

The title compound was synthesized as in Example 37 using methylsulfonyl chloride (0.8 g, 6.2 mmol) and3-amino-N-(3,4-difluoro-phenyl)-4methoxy-benzamide (1.0 g, 3.6 mmol) togive 0.48 g of benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[(methylamino) sulfonyl]amino]-.Microanalysis: C₁₅H₁₅F₂N₃O₄S. 0.04 CH₂Cl₂.0.91H₂O; calculated: C=46.18;H=4.35; N=10.74. found: C=46.18; H=4.36; N=10.64. MS: M⁺+1=372 Da. ¹HNMR(400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 8.60 (s, 1H), 7.93-7.88 (m, 2H),7.74 (d, 8.4 Hz, 1H), 7.52-7.50 (m, 1H), 7.36 (q, J=9.4, 10.4 Hz, 1H),7.13 (d, J=8.7 Hz, 2H), 3.88 (s, 3H), 2.49 (s, 3H).

Example 39 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-(4-pyridinyl)propyl ester

The title compound was synthesized as in Example 1 using3-(4-pyridyl)-1-propanol (0.55 g, 4.0 mmol), CSI (0.42 mL, 4.9 mmol),and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.0 g, 3.6mmol) to give 0.08 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-(4-pyridinyl)propyl ester. Microanalysis: C₂₃H₂₂F₂N₄O₆S.0.08C₆H₁₆NCl.0.48 H₂O; calculated: C=52.21; H=4.52; N=10.58. found: C=52.20;H=4.53; N=10.30. MS: M⁺+1=521 Da. Mp 160-164° C. ¹HNMR (400 MHz,DMSO-d₆) δ 11.33 (s, 1H), 10.15 (s, 1H), 8.48 (s, 1H), 7.91-7.86 (m,3H), 7.50-7.17 (m, 6H), 4.05 (t, J=6.5 Hz, 2H), 3.81 (s, 3H), 2.65 (t,J=7.2 Hz, 2H), 1.89 (t, J=6.5 Hz, 2H).

Example 40 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-2-phenylethylester

The title compound was synthesized as in Example 1 using phenethylalcohol (0.48 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.75 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-2-phenylethylester. Microanalysis: C₂₄H₂₁F₂N₃O₅S.0.1 C₆H₁₆NCl.0.17 H₂O; calculated:C=57.00; H=4.46; N=8.33. found: C=57.00; H=4.33; N=8.27. MS: M⁺+1=502Da. Mp 180-182° C. ¹HNMR (400 Mz, DMSO-d₆) δ 11.65 (s, 1H), 11.47 (s,1H), 9.30 (s, 1H), 7.70 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.50-7.45 (m,1H), 7.32-7.27 (m, 1H), 7.24-7.12 (m, 6H), 6.74 (s, 1H), 4.24 (t, J=7.0Hz, 2H ), 3.74 (s, 3H), 2.85 (t, J=7.0 Hz, 2H).

Example 41 Carbamic Acid,[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-phenylethyl ester

The title compound was synthesized as in Example 1 using phenethylalcohol (0.48 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.0 g, 3.6 mmol) togive 1.16 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]-amino]sulfonyl]-,2-phenylethyl ester. Microanalysis: C₂₃H₂₁F₂N₃O₆S.0.2 C₆H₁₆NCl.0.14 H₂O;calculated: C=54.27; H=4.61; N=837. found: C=54.27; H=4.33; N=8.21. MS:M⁺+1=506 Da. Mp 173-177° C. 1HNMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H),10.34 (s, 1H), 9.41 (s, 1H), 7.94-7.87 (m, 3H), 7.54-7.51 (m, 1H),7.43-7.36 (q, J=9.2, 10.1 Hz, 1H), 7.26-7.16 (m, 6H), 4.24 (t, J=6.8 Hz,2H), 3.78 (s, 3H), 2.86 (t, J=6.8 Hz, 2H).

Example 42 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,Phenylmethyl Ester

The title compound was synthesized as in Example 1 using benzyl alcohol(0.44 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide (1.0 g, 3.6 mmol) togive 1.0 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,phenylmethyl ester. Microanalysis: C₂₂H₁₉F₂N₃O₆S; calculated: C=53.77;H=3.90; N=8.55. found: C=53.49; H=3.83; N=8.63. MS: M⁺+1=492 Da. Mp173-176° C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 10.33 (s, 1H),9.53 (s, 1H), 7.95-7.86 (m, 3H), 7.54-7.51 (m, 1H), 7.44-730 (m, 6H),7.18 (d, J=8.7 Hz, 1H), 5.15 (s, 2H), 3.77 (s, 3H).

Example 43 Acetic Acid,[[[[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]amino]carbonyl]oxy]-,Methyl ester

The title compound was synthesized as in Example 1 using methylglycolate (0.36 g, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.28 g of acetic acid,[[[[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]amino]carbonyl]oxy]-,methyl ester. Microanalysis: C₁₉H₁₇F₂N₃O₇S.0.55 C₄H₈O₂.0.12 H₂O;calculated: C=48.95; H=3.96; N=8.07. found: C=48.95; H=3.92; N=8.07. MS:M⁺+1=470 Da. Mp 190-192° C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H),11.62 (s, 1H), 9.49 (s, 1H), 7.70 (s, 1H), 7.66 (d, J=8.7 Hz, 1H),7.50-7.45 (m, 1H), 7.32-7.27 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.77 (s,1H), 4.72 (s, 2H), 3.79 (s, 3H), 3.65 (s, 3H).

Example 44 Acetic Acid,[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]-amino]sulfonyl]amino]carbonyl]oxy]-,Methyl ester

The title compound was synthesized as in Example 1 using methylglycolate (0.36 g, 4.0 mmol), CSI (0.42 mL 4.9 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.0 g, 3.6 mmol) togive 0.55 g of acetic acid,[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]amino]carbonyl]oxy]-,methyl ester. Microanalysis: C₁₈H₁₇F₂N₃O₈S; calculated: C=45.67; H=3.62;N=8.88; found: C=45.43; H=3.46; N=8.95. MS: M⁺+1=474 Da. Mp 177-180° C.¹HNMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.31 (s, 1H), 9.58 (s, 1H),7.94-7.86 (m, 3H), 7.53-7.51 (m, 1H), 7.40 (q, J=10.4, 9.2 Hz, 1H), 7.19(d, J=8.7 Hz, 1H), 4.70 (s, 2H), 3.83 (s, 3H), 3.65 (s, 3H).

Example 45 Carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-3-hydroxypropylester

Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-3-(phenylmethoxy)propylester (0.25 g, 0.5 mmol) and a catalytic amount of 20% palladium oncarbon were stirred together in methanol under an atmosphere ofhydrogen. After 1.5 hours, the methanol mixture was filtered throughCelite, and the filtrate was concentrated under reduced pressure to givea clear oil. The oil was triturated with diethyl ether, resulting in aprecipitate of 0.11 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl-2-methoxyphenyl]amino]sulfonyl]-3-hydroxypropylester. Microanalysis: C₁₉H₁₉F₂N₃O₆S; calculated: C=50.11; H=4.21;N=9.23. found: C=49.71; H=4.26; N=8.90. MS: M⁺+1=456 Da. ¹HNMR (400 MHz,DMSO-d₆) δ 11.64 (s, 1H), 11.36 (s, 1H), 9.32 (s, 1H), 7.69 (s, 1H),7.65 (d, J=8.7 Hz, 1H), 7.50-7.46 (m, 1H), 7.32-7.27 (m, 1H), 7.15 (d,J=8.4 Hz, 1H), 6.73 (s, 1H); 4.52 (s, 1H), 4.13 (t, J=6.5 Hz, 2H), 3.79(s, 3H), 3.43 (t, J=6.0 Hz, 2H), 1.73-1.67(m, 2H).

Example 46 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-hydroxypropyl ester

The title compound was synthesized as in Example 45 using carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-(phenylmethoxy)propyl ester (0.25 g, 0.40 mmol) to give 0.18 g ofcarbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]-amino]sulfonyl]-,3-hydroxypropyl ester. Microanalysis: C₁₈H₁₉F₂N₃O₇S; calculated:C=47.06; H=4.17; N=9.15. found: C=46.79; H=4.16; N=9.04. MS: M⁺+1=460Da. Mp 178-179° C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.32 (s,1H), 9.42 (s, 1H), 7.94-7.85 (m, 3H), 7.52-7.51 (m, 1H), 7.40 (q, J=9.2,9.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 4.51 (s, 1H), 4.11 (t, J=6.5 Hz,2H), 3.83 (s, 3H), 3.42 (t, J=6.0 Hz, 2H), 1.72-1.66 (m, 2H).

Example 47 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-,2-ethoxyethyl ester

The title compound was synthesized as in Example 1 using 2-ethoxyethanol(0.40 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.43 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,2-ethoxyethyl ester. Microanalysis: C₂₀H₂₁F₂N₃O₆S; calculated: C=51.17;H=4.51; N=8.95. found: C=51.18; H=4.55; N=8.81. MS: M⁺+1=470 Da. Mp178-181C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 11.53 (s, 1H), 9.32(s, 1H), 7.71 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.51-7.47 (m, 1H),733-729 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.75 (s, 1H), 4.20-4.18 (m,2H), 3.81 (s, 3H), 3.55-3.53 (m, 2H), 3.40-3.37 (m, 2H), 1.06-1.02 (m,3H).

Example 48 Carbamic Acid,[[[5[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-ethoxyethyl ester

The title compound was synthesized as in Example 1 using 2-ethoxyethanol(0.40 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4methoxy-benzamide (1.0 g, 3.6 mmol) togive 0.95 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]-amino]sulfonyl]-,2-ethoxyethyl ester. Microanalysis: C₁₉H₂₁F₂N₃O₇S; calculated: C=48.20;H=4.47; N=8.88. found. C=48.29; H=4.48; N=8.80. MS: M⁺+1=474 Da. Mp179-182° C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H), 10.34 (s, 1H),9.44 (s, 1H), 7.96-7.87 (m, 3H), 7.54-7.52 (m, 1H), 7.42 (q, J=10.1, 9.2Hz, 1H), 720 (d, J=8.4 Hz, 1H), 4.18 (t, J=43 Hz, 2H), 3.85 (s, 3H),3.54 (t, J=4.6 Hz, 2H), 3.41 (q, J=7.0 Hz, 2H), 1.06 (t, J=7.0 Hz, 3H).

Example 49 Carbamic Acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-3-(phenylmethoxy)propylester

The title compound was synthesized as in Example 1 using3-benzyloxy-1-propanol (0.65 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.84 g of carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)₂-methoxyphenyl]amino]sulfonyl]-3-(phenylmethoxy)propylester. Microanalysis: C₂₆H₂₅F₂N₃O₆S; calculated: C=57.24; H=4.62;N=7.70; found: C=56.93; H=4.61; N=7.84. MS: M⁺+1=546 Da. Mp 166-168° C.¹HNMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 11.40 (s, 1H), 9.32 (s, 1H),7.68 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.48-7.43 (m, 1H), 7.30-7.22 (m,6H), 7.11 (d, J=8.4 Hz, 1H), 6.72 (s, 1H), 4.35 (s, 2H), 4.12 (t, J=6.3Hz, 2H), 3.75 (s, 3H), 3.41 (t, J=6.0 Hz, 2H), 1.84-1.78 (m, 2H).

Example 50 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-(phenylmethoxy)propyl ester

The title compound was synthesized as in Example 1 using3-benzyloxy-1-propanol (0.65 mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide (1.0 g, 3.6 mmol) togive 1.11 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,3-(phenylmethoxy)propyl ester. Microanalysis: C₂₅H₂₅F₂N₃O₇S; calculated:C=54.21; H=4.64; N=7.59. found: C=54.21; H=4.60; N=7.72. MS: M⁺+1=550Da. Mp 178-179° C. ¹HNMR (400 Mz, DMSO-d₆) δ 11.40 (s, 1H), 10.33 (s,1H), 9.44 (s, 1H), 7.96-7.87 (m, 3H), 7.54 (m, 1H), 7.53 (q, J=2.2, 1.7Hz, 1H), 7.43-7.25 (m, 6H), 7.19 (d, J=8.7 Hz, 1H), 4.43 (s, 2H), 4.16(t, J=6.5 Hz, 2H), 3.83 (s, 3H), 3.47 (t, J=6.3 Hz, 2H), 1.06 (m, 2H).

Example 51 Carbamic Acid,[[[5-(5,6-difluoro-IH-indo-2yl)-methoxyphenyl]amino]-sulfonyl]-hexylester

The title compound was synthesized as in Example 1 using hexanol (0.50mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (1.0 g, 3.6 mmol)to give 0.79 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-hexylester. Microanalysis: C₂₂H₂₅F₂N₃O₅S; calculated: C=54.88; H=5.23;N=8.73; found: C=55.05; H=5.14; N=8.64. MS: M⁺+1=482 Da. Mp 186-188° C.¹HNMR (400 Mz, DMSO-d₆) δ 11.66 (s, 1H), 9.27 (s, 1H), 7.72 (s, 1H),7.66 (d, J=6.8 Hz, 1H), 7.52-7.47 (m, 1H), 7.34-7.30 (m, 1H), 7.17 (d,J=8.7 Hz, 1H), 6.76 (s, 1H), 4.08-4.05 (m, 2H), 3.82 (s, 3H), 1.55-1.50(m, 2H), 1.22 (s, 6H), 0.84-0.80 (m, 3H).

Example 52 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2methoxyphenyl]amino]sulfonyl]-,Hexyl ester

The title compound was synthesized as in Example 1 using hexanol (0.50mL, 4.0 mmol), CSI (0.42 mL, 4.9 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.0 g, 3.6 mmol) togive 0.76 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,hexyl ester. Microanalysis: C₂₁H₂₅F₂N₃O₆S; calculated: C=51.95; H=5.19;N=8.65. found: C=51.90; H=5.09; N=8.40. MS: M⁺+1=486 Da. Mp 175-178° C.¹HNMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 10.31 (s, 1H), 9.33 (s, 1H),7.96-7.88 (m, 3H), 7.56-7.54 (m, 1H), 7.42 (q, J=92, 8.9 Hz, 1H), 7.21(d, J=8.7 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.87 (s, 3H), 1.55-1.54 (m,2H), 1.26 (s, 6H), 0.86-0.84 (m, 3H).

Example 53 Carbamic Acid,[[[5-(5,6-difluoro-indol-2-yl)-2-methoxyphenyl]amino]-sulfonyl]-,1,1-dimethylethyl ester

The title compound was synthesized as in Example 1 using t-butyl alcohol(2.0 mL, 20.9 mmol), CSI (2.0 mL, 23.0 mmol), and5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (2.5 g, 9.1 mmol)to give 3.28 g of carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,1,1-dimethylethyl ester. Microanalysis: C₂₀H₂₁F₂N₃O₅S.0.06 C₆H₁₆NCl.0.22H₂O; calculated: C=52.97; H=4.85; N=9.20. found: C=52.51; H=4.85;N=9.20. MS: M⁺+1=454 Da. Mp 158-160° C. ¹HNMR (400 MHz, DMSO-d₆) δ 11.64(s, 1H), 11.17 (s, 1H), 8.99 (s, 1H), 7.71 (s, 1H), 7.61 (d, J=6.5 Hz,1H), 7.51-7.46 (m, 1H), 7.32-7.28 (m, 1H), 7.15 (d, J=8.7 Hz, 1H), 6.72(s, 1H), 3.82 (s, 3H), 1.36 (s, 9H).

Example 54 Sulfamide, [5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]

Carbamic acid,[[[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-1,1-dimethylethylester (2.0 g, 4.4 mmol) and anisole (1.5 mL, 13.8 mmol) were stirred intrifluoroacetic acid (20 mL) for 0.5 hour. The excess trifluoroaceticacid was evaporated under reduced pressure to give a white solid, whichwas triturated with ether and dried. Yield 1.14 g of sulfamide,[5-(5,6-difluoro-IH-indol-2-yl)-2-methoxyphenyl]-. Microanalysis:C₁₅H₁₃F2N₃O₃S; calculated: C=50.99; H=3.71; N=11.89; found: C=50.90;H=3.83; N=11.50. MS: M⁺+1=354 Da. Mp 177-180° C.

Example 55 Benzamide,3-[(aminosulfonyl)amino]-N-(3,4-difluorophenyl)-4-methoxy

Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,1,1-dimethylethyl ester (0.28 g, 0.6 mmol) and anisole (0.33 mL, 3.1mmol) were stirred in trifluoroacetic acid (10 mL) for 0.5 hour. Theexcess trifluoroacetic acid was evaporated under reduced pressure togive a white solid, which was triturated with ether and dried. Yield0.16 g of benzamide,3-[(aminosulfonyl)amino]-N-(3,4-difluorophenyl)-4methoxy-.Microanalysis: C₁₄H₁₃F₂N₃O₄S; calculated: C=46.04; H=3.52; N=11.36;found: C=46.02; H=3.60; N=11.36. MS: M⁺⁺1=358 Da. Mp 167-170° C.

Example 56 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl ester

The title compound was synthesized as in Example 1 using N-hydroxyethylphthalimide (2.2 g, 11.5 mmol), CSI (1.0 mL, 11.5 mmol), and3-amino-N-(3,4-difluorophenyl-4-methoxy-benzamide (1.5 g, 5.4 mmol) togive 0.98 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-ethyl ester. Microanalysis:C₂₅H₂₀F₂N₄O₈S; calculated: C=51.68; H=3.59; N=9.64. found: C=51.69;H=3.38; N=9.61. MS: M⁺+1=575 Da. Mp 203-205° C. ¹HNMR (400 MHz, DMSO-d₆)δ 11.42 (s, 1H), 10.30 (s, 1H), 9.38 (s, 1H), 7.93-7.80 (m, 7H),7.52-7.50 (m, 1H), 7.39 (q, J=9.2, 10.6 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H),429 (t, J=5.8 Hz, 2H), 3.84 (t, J=5.8 Hz, 2H), 3.80(s, 3H).

Example 57 Benzamide,N-(3,4-difluorophenyl-3-[[[[(dimethylamino)sulfonyl]-amino]-carbonyl]amino]-4-methoxy

3-Amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (2.0 g, 7.2 mmol)was dissolved in 50 mL of methylene chloride and cooled to 0° C.Chlorosulfonyl isocyanate (0.85 mL, 9.8 mmol) dissolved in 20 mL ofmethylene chloride was added dropwise. The mixture was stirredovernight. The resulting solid was collected by filtration and driedunder vacuum. The dried solid (1.0 g, 2.4 mmol) was sited in 50 mL ofmethylene chloride with triethylamine (0.7 mL, 4.8 mmol) for 1 hour.Dimethylamine (1.2 mL of a 2N solution, 2.4 mmol) was added, and thesolution stirred for 48 hours. The resulting mixture was washed withwater (2×50 mL) and the organic phase dried over magnesium sulfate. Thesolvents were evaporated under reduced pressure to give a foam. The foamwas redissolved in a small amount of fresh methylene chloride andtreated with 1N hydrochloric acid (20 mL). Vigorous shaking produced aprecipitate, which was collected via filtration. The resulting powderwas sequentially triturated with water, methylene chloride, and ether.The triturated solid was dried under vacuum to give 0.64 g of benzamide,N-(3,4-difluorophenyl)-3-[[[[(dimethylamino)sulfonyl]-amino]carbonyl]amino]-4-methoxy-.Microanalysis: C₁₇H₁₈F₂N₄O₅S-0.86 H₂O; calculated: C=46.00; H=4.31;N=12.69. found: C=46.00; H=4.31; N=12.69. MS:M⁺+1=349 Da. Mp 253-255° C.¹HNMR (400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 10.25 (s, 1H), 9.26 (s, 1H),7.94-7.89 (m, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.49-7.39 (m,2H), 7.27 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 2.95 (s, 6H).

Example 58 Carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,1,1-dimethylethyl ester

The title compound was synthesized as in Example 1 using t-butyl alcohol(1.8 mL, 19.1 mmol), CSI (2.0 mL, 23.0 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (5.3 g, 19.1 mmol)to give 0.84 g of carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]-,1,1-dimethylethyl ester. Microanalysis: C₁₉H21F₂N₃O₆S; calculated:C=49.89; H=4.63; N=9.19. found: C=49.81; H=4.48; N=9.14. MS: M⁺+1=456Da. Mp 193-194° C.

Example 59 Benzamide,N-(3,4-difluorophenyl)-3-[[[[[[4-(1,1-dimethylethyl)phenyl]-amino]carbonyl]amino]sulfonyl]amino]-4-methoxy

The title compound was synthesized as in Example 1 using 4-t-butylaniline (1.3 mL, 8.1 mmol), CSI (0.85 mL, 9.8 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.9 g, 6.8 mmol) togive 0.095 g of benzamide,N-(3,4-difluorophenyl)-3-[[[[[[4-(1,1-dimethylethyl)phenyl]amino]carbonyl]amino]sulfonyl]amino]-4-methoxy-.Microanalysis: C₂₅H₂₆F₂N₄O₅S._(0.46) H₂O; calculated: C=55.52; H=5.02;N=10.36. found: C=55.46; H=4.94; N=10.40. MS: M⁺+1=533 Da. Mp 199-202°C.

Example 60 Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(3-nitrophenyl)-amino]carbonyl]amino]sulfonyl]amino]

The title compound was synthesized as in Example 1 using 3-nitroaniline(1.35 g, 9.8 mmol), CSI (0.85 L, 9.8 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.39 g, 1.4 mmol)to give 0.074 g of benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(3-nitrophenyl)-amino]carbonyl]-amino]sulfonyl]amino]-.Microanalysis: C₂₁H₁₇F₂N₅O₇S.0.44 H₂O; calculated: C=47.65; H=3.40;N=13.23. found: C=47.64; H=3.01; N=13.51. MS: M⁺+1=522 Da.Mp 206-208° C.

Example 61 Benzamide,3-[[[[[(3-chlorophenyl)amino]carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy

The title compound was synthesized as in Example 1 using 3-chloroaniline(2.0 mL, 18.9 mmol), CSI (2.0 mL, 23.0 mmol), and3-amino-N-(3,4difluoro-phenyl)-4-methoxy-benzamide (1.39 g, 5.0 mmol) togive 0.030 g of benzamide,3-[[[[[(3-chlorophenyl)amino]carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-.Microanalysis: C₂₁H₁₇ClF₂N₄O₅S; calculated: C=49.37; H=3.35; N=10.97.found: C=48.97; H=3.11; N=10.78. MS: M⁺+1=511 Da. Mp 193-196° C.

Example 62 Benzamide,3-[[[[[[3,5-bis(trifluoromethyl)phenyl]amino]-carbonyl]amino]-sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy

The title compound was synthesized as in Example 1 using3,5-bis(trifluoromethyl)aniline (1.3 mL, 8.2 mmol), CSI (0.85 mL, 9.8mmol), and 3-amino-N-(3,4-difluorophenyl)-4-methoxy-benzamide (0.63 g,2.3 mmol) to give 0.032 g of benzamide,3-[[[[[[3,5-bis(trifluoromethyl)phenyl]amino]-carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-.Microanalysis: C₂₃H₁₆F₈N₄O₅S.1.63 H₂O; calculated: C=43.04; H=3.02;N=8.73. found: C=43.05; H=2.68; N=8.55. MS: M⁺−1=611 Da. Mp 175-178° C.

Example 63 Benzamide,3-[[[[[(4-aminophenyl)amino]carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-,mono(trifluoroacetate)

Chlorosulfonyl isocyanate (1.0 mL, 12.0 mmol) was dissolved in 20 mL ofmethylene chloride and cooled to 0° C. BOC-1,4-Phenylenediamine (2.5 g,12.0 mmol) dissolved in 20 mL of methylene chloride was added dropwiseto the chlorosulfonyl isocyanate solution. Upon stirring, a precipitateslowly formed. After 2 hours, the mixture was filtered, and the solidcollected and dried. Yield 2.92 g. A portion of this solid (0.92 g, 2.7mmol) was placed in a flask containing3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.75 g, 2.7 mmol),triethylamine (1.0 mL, 6.8 mmol) and 50 mL of tetrahydrofuran. Themixture was heated to 50° C., and sired overnight The tetrahydrofuranwas removed under reduced pressure; the resulting solid was trituratedwith methanol and dried under vacuum. Yield 0.32 g. A portion of thissolid (0.20 g, 0.3 mmol) was stirred with anisole (0.4 mL, 3.7 mmol) intrifluoroacetic acid (20 mL). After stirring for 1 hour, thetrifluoroacetic acid was removed under reduced pressure. The resultingoil was triturated with ether, resulting in a solid. The solid was driedunder vacuum; yield 0.20 g of benzamide,3-[[[[[(4-aminophenyl)amino]carbonyl]-amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-,mono(trifluoroacetate). Microanalysis: C₂₁H₁₉F₂N₅O₅S.0.69 C₂HO₂F₃.2.6H₂O; calculated: C=43.62; H=3.96; N=11.36. found: C=43.99; H=3.56;N=11.20. Mp 18& 189° C.

Example 64 Benzamide,N-(3,4-difluorophenyl)methoxy-3-[[[[[[3-(trifluoromethyl)phenyl]amino]carbonyl]amino]sulfonyl]amino]

The title compound was synthesized as in Example 1 using3-trifluoromethylaniline (1.32 g, 10.6 mmol), CSI (0.85 mL, 9.8 mmol),and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.92 g, 3.3mmol) to give 0.060 g of benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[[3-(trifluoromethyl)phenyl]amino]carbonyl]amino]sulfonyl]amino]-.Microanalysis: C₂₂H₁₇F₅N₄O₅S; calculated: C=48.53; H=3.15; N=10.29.found: C=48.52; H=3.09; N=10.18. MS: M⁺+1=545 Da. Mp 198-200° C.

Example 65 Benzoic Acid,4-[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]amino]carbonyl]amino]

Chlorosulfonyl isocyanate (1.7 mL, 19.5 mmol) was dissolved in 20 mL ofmethylene chloride and cooled to 0° C. Methyl 4-aminobenzoate (2.5 g,16.2 mmol) dissolved in 20 mL of methylene chloride was added dropwiseto the chlorosulfonyl isocyanate solution. Upon stirring, a precipitateslowly formed. After 2 hours, the mixture was filtered, and the solidcollected and dried; yield 4.21 g. A portion of this solid (1.0 g, 3.4mmol) was placed in a flask containing3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.95 g, 3.4 mmol),triethylamine (1.2 mL, 8.5 mmol), and 50 mL of tetrahydrofuran. Themixture was stirred overnight. The tetrahydrofuran was evaporated underreduced pressure, and the resulting solid was dissolved in methylenechloride (50 mL). The methylene chloride was sequentially washed with 25mL of 1N hydrochloric acid, water, and brine. A precipitate was formed,which was recovered by filtration and triturated with a mixture ofmethylene chloride and methanol. The solid was dried under vacuum; yield0.67 g. A portion of this solid (0.30 g, 0.6 mmol) was suspended in a9:1 mixture of tetrahydrofuran and water (10 mL). Lithium hydroxide(48.3 mg, 2.0 mmol) was added, and the resulting mixture was refluxedovernight. The mixture was diluted with 1N hydrochloric acid (50 mL) andextracted with diethyl ether (1×50 mL) and ethyl acetate (1×50 mL). Theorganics were combined, dried with magnesium sulfate, and filtered. Theresulting filtrate was evaporated under reduced pressure to give a whitefoam. The foam was triturated with hot ethyl acetate and ether, thendried under vacuum to give 0.12 g of benzoic acid,4-[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]amino]carbonyl]amino]-.Microanalysis for C₂₂H₁₈F₂N₄O₇S.0.25 H₂O.0.1 C₄H₈O₂; calculated C=50.40;H=3.64; N=10.50. found: C=50.29; H=3.71; N=10.14.

Example 66 Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)-amino]carbonyl]amino]sulfonyl]amino]

The title compound was synthesized as in Example 1 using p-anisidine(1.0 g, 7.1 mmol), CSI (0.85 mL, 9.8 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.75 g, 6.3 mmol)to give 0.43 g of benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[[(4-methoxyphenyl)amino]-carbonyl]amino]sulfonyl]amino]-.Microanalysis: C₂₂H₂₀F₂N₄O₆S; calculated: C=52.17; H=3.98; N=11.06.found: C=52.17; H=3.89; N=10.95. Mp 189-192° C.

Example 67 Benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)carbonyl]-amino]sulfonyl]amino]

The title compound was synthesized as in Example 1 using p-toluidine(0.87 g, 8.1 mmol), CSI (0.85 mL, 9.8 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.56 g, 2.0 mmol)to give 0.25 g of benzamide,N-(3,4-difluorophenyl)-4-methoxy-3-[[[[(phenylamino)carbonyl]amino]-sulfonyl]amino]-.Microanalysis: C₂₂H₂₀F₂N₄O₅S; calculated: C=53.87; H=4.11; N=11.42.found: C=53.56; H=4.14; N=11.27. MS: M⁺+1=491 Da. Mp 194-197° C.

Example 68 Benzamide,3-[[[[[(4-chlorophenyl)amino]carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy

The title compound was synthesized as in Example 1 using 4-chloroaniline(1.0 g, 8.1 mmol), CSI (0.85 mL, 9.8 mmol), and3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.17 g, 4.2 mmol)to give 0.24 g of benzamide,3-[[[[[(4-chlorophenyl)amino]carbonyl]amino]sulfonyl]amino]-N-(3,4-difluorophenyl)-4-methoxy-.Microanalysis: C₂₁H₁₇ClF₂N₄O₅S; calculated: C=49.37; H=3.35; N=10.97.found: C=49.15; H=3.17; N=10.70. MS: M⁺+1=511 Da. Mp 195-198° C.

Example 69 Carbamic Acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]methyl-,Ethyl ester

The title compound was synthesized as in Example 13 using carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]-,ethyl ester (1.0 g, 2.3 mmol), DBU (0.43 g, 1.2 eq, 2.8 mmol), andmethyl iodide (0.29 mL, 2 eq, 4.7 mmol) to give carbamic acid,[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]sulfonyl]methyl-,ethyl ester as a white solid. Microanalysis: C₁₈H₁₉F₂N₃O₆S₁; calculated:C=48.76; H=4.32; N=9.48. found: C=48.76; H=4.25; N=9.30. MS: M⁺+1=444Da.

Examples of assays useful for characterizing the biological effects ofthe compounds of the present invention on the 15-LO cascade aredescribed below.

Biological Example 1

Rabbit Reticulocyte 15-LO Assay (H15LO)

The H15LO assay measures inhibition of 15-LO catalyzed oxidation oflinoleic acid to the hydroperoxy fatty acid 13-(S)HPODE, a conjugateddiene. In the H15LO assay, a test compound was incubated with 15-LOenzyme in the presence of the linoleic acid substrate. For example, 2units (U) of rabbit reticulocyte 15-LO and 174 μM linoleic acid wereincubated with a known amount of a test compound of the presentinvention for 15 minutes at 4° C. The total reaction volume was 100 μLin phosphate buffer saline (PBS) containing 0.2% sodium cholate. Thereaction was stopped with 100 μL of mobile phase and 10 mL of triethylphosphite. The resulting 13-(S)HPODE was essentially quantitativelyreduced with triethyl phosphite to the more stable13-hydroxyoctadecadienoate (13-HODE), which prevents artificial,nonenzymatic lipidperoxidation and product breakdown in the sample.13-HODE was quantitated by comparing peak areas of individual sampleswith those from a standard curve generated using authentic 13-HODE. Thetest reaction was compared to a control reaction, which was identical tothe test reaction except no test compound of the present invention waspresent Percent inhibition was calculated as the amount of 13-HODEproduced by the test reaction divided by the amount of 13-HODE producedby the control reaction, expressed as a percent The results for certaincompounds of the present invention are reported below in Table 1 in thecolumn headed “H15LO IC₅₀ (nM)” as an IC₅₀ in nM or the concentration ofcompound of the present invention in nanomolar required to inhibit 15-LOcatalyzed oxidation by 50%.

15-LO is obtained from phenylhydrazine-treated rabbits and purifiedaccording to the method of Rapoport (Rapoport et al., European Journalof Biochemistry, 1979;96:545-561).

Biological Example 2

Monocyte Recruitment

The recruitment or chemotaxis of monocytes is assayed by methods wellknown to those skilled in the art. In particular, the method set forthin J. Clin. Invest., 1988;82:1853-1863, which is hereby incorporated byreference, can be used.

Biological Example 3

Human Lysate 15-LO Assay (HUM15LO)

The HUM15LO assay measures inhibition of 15-LO catalyzed oxidation oflinoleic acid to the hydroperoxy fatty acid 13-(S)HPODE, a conjugateddiene. In the HUM15LO assay, a test compound of the present inventionwas incubated with 15-LO enzyme in the presence of the linoleic acidsubstrate. For example, a known amount of a test compound of the presentinvention, 100 μL of human 15-LO, and 174 μM linoleic acid in PBScontaining 0.2% sodium cholate were incubated for 15 minutes at 4° C.The reaction was stopped with 100 μL of mobile phase and 10 μL oftriethyl phosphite. 13-(S)HPODE was essentially quantitatively reducedwith triethyl phosphite to the more stable 13-hydroxyoctadecadienoate(13-HODE), which prevents artificial, nonenzymatic lipidperoxidation andproduct breakdown in the sample. 13-HODE was quantitated by comparingpeak areas of individual samples with those from a standard curvegenerated using authentic 13-HODE. The test reaction is compared to acontrol reaction, which is identical to the test reaction except no testcompound of the present invention is present Percent inhibition iscalculated as the amount of 13-HODE produced by the test reactiondivided by the amount of 13-HODE produced by the control reaction,expressed as a percent. The results for certain compounds of the presentinvention are reported below in Table 1 in the column headed “HUM15LOIC₅₀ (nM)” as an IC₅₀ in nM or the concentration of compound of thepresent invention in nanomolar required to inhibit 15-LO catalyzedoxidation by 50%.

Human 15-LO was generated in a recombinant 15-lipoxygenase bacculovirusexpression system, using Gibco/BRL/Life Technologies' Bac-to-Bacexpression reagents; T4 DNA ligase, Kanamycin, Gentamicin, tetracycline,penicillin, streptomycin, Bluo-gal, IPTG, DH10Bac competent cells, SOC,LB medium, Sf-900 II SFM media, Sf9 insect cells, Cell Fectin, andEcoRI, BamHI and KpnI restriction enzymes.

TABLE 1 HUM15LO H15LO Ex. IC₅₀ (nM) IC₅₀ (nM) 20 1050 N/A 17 37 10 18142 N/A 19 339 N/A 24 33 11 25 34 15 26 630 N/A 68 359 N/A 67 182 N/A 66225 51 65 273 30 64 24 N/A 29 85 47 23 255 N/A 22 25 25 21 14  9 63 214N/A 62 173 N/A 61 39 13 60 25 N/A 59 24 13 58 751 N/A 57 N/A N/A 56 341N/A 55 29 19 54 12 10 53 N/A 23 2 384 N/A 3 408 N/A 4 144 N/A 52 39  551 12  2 50 65 18 49 15  5 48 306 N/A 47 54 44 5 240 N/A 69 154 N/A 46830 N/A 45 133 80 44 236 N/A 43 30 17 42 76 19 41 69 13 6 N/A N/A 40 15 7 7 79 N/A 8 312 N/A 9 154 N/A 39 N/A N/A 37 7  5 38 13 13 36 13 12 10N/A N/A 11 N/A N/A 35 N/A N/A 34 30 26 33 N/A N/A 32 16  6 27 44 23 2818 39 12 N/A N/A 1 6 17 13 30 12 14 N/A N/A 15 N/A N/A 33 13  7 30 14  516 10  2 N/A = datum not available.E. Uses

The disclosed compounds of Formula I will be formulated by standardmethods into pharmaceutical compositions that are useful as prophylacticor therapeutic treatments for diseases modulated by the 15-LO cascade.The compositions will be administered to mammals for treating diseaseswith an inflammatory component, including inflammation andatherosclerosis.

1. Dosages

Those skilled in the art will be able to determine, according to knownmethods, the appropriate dosage for a patient, taking into accountfactors such as age, weight, general health, the type of pain requiringtreatment, and the presence of other medications. In general, aneffective amount will be between 0.1 and 1000 mg/kg per day, preferablybetween 1 and 400 mg/kg body weight, and daily dosages will be between10 and 5000 mg for an adult subject of normal weight The dosages,however, may be varied depending upon the requirements of the patient,the severity of the condition being treated, and the compound beingemployed. Determination of the proper dosage for a particular situationis within the skill of the art. Generally, treatment is initiated withsmaller dosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

2. Formulations

Dosage unit forms include tablets, capsules, pills, powders, granules,aqueous and nonaqueous oral solutions and suspensions, and parenteralsolutions packaged in containers adapted for subdivision into individualdoses. Dosage unit forms can also be adapted for various methods ofadministration, including controlled release formulations, such assubcutaneous implants. Administration methods include oral, rectal,parenteral (intravenous, intramuscular, subcutaneous), intracisternal,intravaginal, intraperitoneal, intravesical, local (drops, powders,ointments, gels, or cream), and by inhalation (a buccal or nasal spray).

Parenteral formulations include pharmaceutically acceptable aqueous ornonaqueous solutions, dispersion, suspensions, emulsions, and sterilepowders for the preparation thereof. Examples of carriers include water,ethanol, polyols (propylene glycol, polyethylene glycol), vegetableoils, and injectable organic esters such as ethyl oleate. Fluidity canbe maintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and( ) propellants.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

Example 70

Tablet Formulation: Ingredient Amount (mg) The compound of Example 1 25Lactose 50 Cornstarch (for mix) 10 Cornstarch (paste) 10 Magnesiumstearate (1%) 5 Total 100

The compound of Example 1, lactose, and cornstarch (for mix) are blendedto uniformity. The cornstarch (for paste) is suspended in 200 mL ofwater and heated with stirring to form a paste. The paste is used togranulate the mixed powders. The wet granules are passed through a No. 8hand screen and dried at 80° C. The dry granules are lubricated with the1% magnesium stearate and pressed into a tablet. Such tablets can beadministering to a human from one to four times a day for treatment ofdiseases responsive to the inhibition of the enzyme 15-lipoxygenase.

Example 71 Coated Tablets:

The tablets of Example 70 are coated in a customary manner with acoating of sucrose, potato starch, talc, tragacanth, and colorant.

Example 72

Injection Vials:

The pH of a solution of 500 g of the compound of Example 4 and 5 g ofdisodium hydrogen phosphate is adjusted to pH 6.5 in 3 L ofdoubled-distilled water using 2 M hydrochloric acid. The solution issterile filtered, and the filtrate is filled into injection vials,lyophilized under sterile conditions, and aseptically sealed. Eachinjection vial contains 25 mg of the compound of Example 4.

Example 73

Suppositories:

A mixture of 25 g of the compound of Example 6, 100 g of soya lecithin,and 1400 g of cocoa butter is fused, poured into molds, and allowed tocool. Each suppository contains 25 mg of the compound of Example 6.

Example 74

Solution:

A solution is prepared from 1 g of the compound of Example 55, 9.38 g ofNaH₂PO₄.12H₂O, 28.48 g of Na₂HPO₄.12H₂O, and 0.1 g benzalkonium chloridein 940 mL of double distilled water. The pH of the solution is adjustedto pH 6.8 using 2 M hydrochloric acid. The solution is diluted to 1.0 Lwith double-distilled water, and sterilized by irradiation. A 25 mLvolume of the solution contains 25 mg of the compound of Example 55.

Example 75

Ointment:

500 mg of the compound of Example 21 is mixed with 99.5 g of petroleumjelly under aseptic conditions. A 5 g portion of the ointment contains25 mg of the compound of Example 21.

Example 76 Capsules:

Two kilograms of the compound of Example 33 are filled into hard gelatincapsules in a customary manner such that each capsule contains 25 mg ofthe invention compound.

Example 77

Ampoules:

A solution of 2.5 kg of the compound of Example 60 is dissolved in 60 Lof double-distilled water. The solution is sterile filtered, and thefiltrate is filled into ampoules. The ampoules are lyophilized understerile conditions and aseptically sealed. Each ampoule contains 25 mgof the compound of Example 60.

From the above disclosure and examples, and from the claims below, theessential features of the invention are readily apparent. The scope ofthe invention also encompasses various modifications and adaptationswithin the knowledge of a person of ordinary skill. Examples include adisclosed compound modified by addition or removal of a protectinggroup, or the formation of an ester, pharmaceutical salt, hydrate, acid,or amide of a disclosed compound. Publications cited herein are herebyincorporated by reference in their entirety.

Having described the present invention above, various embodiments of theinvention are hereupon claimed.

1. A compound of Formula I:

wherein: R is OH, O—C₁₋₄ alkyl, or halo; X is R₁, OR₁, SR₁, NHR₁, orNR₁R₂, wherein R₁ and R₂ are independently selected from C₁-C₁₂ alkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, benzyl, C₃-C₇ cycloalkyl, and phenyl,wherein: the alkyl, alkenyl, alkynyl, benzyl, and phenyl groups areoptionally substituted with from 1 to 5 substituents independentlyselected from halo, NHR₃, CF₃, C₁-C₆ alkyl, OR₄, CO₂R₃, NO₂, and SR₃,wherein R₃ and R₄ are independently H or C₁-C₆ alkyl; W and V areindependently SO₂ or C═O; R₅ is H, C₁-C₆ alkyl, or benzyl, whereinbenzyl is optionally substituted with R₁, wherein R₁ is as definedabove, or R₅ is a pharmaceutically acceptable cation; Y is NR₆ or O,wherein R₆ is H or C₁-C₆ alkyl; Z is 2-indolyl, or 3-indolyl, which areoptionally substituted with from 1 to 4 substituents independentlyselected from C₁-C₆ alkyl, fluoro, chloro, bromo, iodo, nitro, NHR₇,NR₇R₈, and OR₇, wherein R₇ and R₈ are independently H or C₁-C₆ alkyl;wherein: each hydrocarbyl above is optionally substituted with from 1 to3 substituents independently selected from halo, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, phenyl, hydroxyl, amino,(amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₆ thioalkyl, C₁-C₆ alkoxy,COOH, COO(C₁-C₆ allyl), SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl,di(C₁-C₆ alkyl)amino, and nitro, wherein the alkyl, cycloalkyl, alkenylalkynyl, and phenyl substituents may be optionally substituted with from1 to 3 substituents independently selected from halo, C₁-C₆ alkyl,hydroxyl, amino, and nitro; and pharmaceutically acceptable saltsthereof.
 2. A compound of claim 1, and pharmaceutically acceptable saltsthereof, wherein Z is 2-indolyl, or 3-indolyl, which are optionallysubstituted with from 1 to 4 substituents independently selected fromfluoro, chloro, and methyl.
 3. A compound of claim 2, andpharmaceutically acceptable salts thereof, wherein Z is 2-indolyl, or3-indolyl, which are substituted with from 1 to 3 substituentsindependently selected from halo, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆alkenyl, C₁-C₆ alkyl, phenyl, hydroxyl, amino, (amino)sulfonyl,N-acetyl, O-acetyl, C₁-C₆ thioalkyl, C₁-C₆ alkoxy, COOH, COO(C₁-C₆allyl), SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl, di(C₁-C₆alkyl)amino, and nitro, wherein the alkyl, cycloalkyl, alkenyl, alkynyl,and phenyl substituents may be optionally substituted with from 1 to 3substituents independently selected from halo, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, phenyl, hydroxyl, amino,(amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₆ thioalkyl, C₁-C₆ alkoxy,COOH, COO(C₁-C₆ allyl), SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂, acetyl,di(C₁-C₆ alkyl)amino, and nitro, wherein the alkyl, cycloalkyl, alkenyl,alkynyl, and phenyl substituents may be optionally substituted with from1 to 3 substituents independently selected from halo, C₁-C₆ alkyl,hydroxyl, amino, and nitro.
 4. A compound of claim 1, andpharmaceutically acceptable salts thereof, wherein Z is 2-indolyl, or3-indolyl, which are substituted with from 1 to 3 substituents selectedfrom fluoro, chloro, bromo, and iodo.
 5. A compound of claim 1, andpharmaceutically acceptable salts thereof, wherein Z comprises 2-indolyloptionally substituted with from 1 to 4 substituents independentlyselected from fluoro, chloro, and methyl.
 6. A compound of claim 5, andpharmaceutically acceptable salts thereof, wherein Z is5,6-difluoro-indol-2-yl.
 7. A compound of claim 1, and pharmaceuticallyacceptable salts thereof, wherein R₅ is H.
 8. A compound of claim 1, andpharmaceutically acceptable salts thereof, wherein R₅ is a cationselected from an alkali earth metal cation, an alkaline earth metalcation, ammonium, and choline.
 9. A compound of claim 1, andpharmaceutically acceptable salts thereof, wherein R₅ is sodium cation,potassium cation, choline, or hemi calcium cation.
 10. A compound ofclaim 1, and pharmaceutically acceptable salts thereof, wherein W isSO₂.
 11. A compound of claim 1, and pharmaceutically acceptable saltsthereof, wherein X is R₁, OR₁, SR₁, NHR₁, or NR₁R₂, wherein R₁ and R₂are independently selected from C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, benzyl, C₃-C₆ cycloalkyl, and phenyl, wherein the alkyl,alkenyl, alkynyl, benzyl and phenyl groups are optionally substitutedwith from 1 to 3 substituents independently selected from halo, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, phenyl, hydroxyl,amino, (amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₆ thioalkyl, C₁-C₆alkoxy, COOH, COO(C₁-C₆ allyl), SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂,acetyl, di(C₁-C₆ alkyl)amino, and nitro, wherein the alkyl, cycloalkyl,alkenyl, alkynyl, and phenyl substituents may be optionally substitutedwith from 1 to 3 substituents independently selected from halo, C₁-C₆alkyl, hydroxyl, amino, and nitro.
 12. A compound of claim 1, andpharmaceutically acceptable salts thereof, wherein X is R₁, OR₁, NHR₁,or NR₁R₂, wherein R₁ and R₂ are independently selected from C₂-C₅ alkyl,C₂-C₅ alkenyl, C₂-C₅ alkynyl, benzyl, and phenyl, wherein the alkyl,alkenyl, alkynyl, benzyl, and phenyl groups are optionally substitutedwith from 1 to 3 substituents independently selected from halo, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, phenyl, hydroxyl,amino, (amino)sulfonyl, N-acetyl, O-acetyl, C₁-C₆ thioalkyl, C₁-C₆alkoxy, COOH, COO(C₁-C₆ allyl), SO₃Na, SO₃H, SO₂NH₂, cyano, CH₂NH₂,acetyl, di(C₁-C₆ alkyl)amino, and nitro, wherein the alkyl, cycloalkyl,alkenyl, alkynyl, and phenyl substituents may be optionally substitutedwith from 1 to 3 substituents independently selected from halo, C₁-C₆alkyl, hydroxyl, amino, and nitro.
 13. A compound of claim 1, wherein Xis a phenylamino, phenoxy, alkoxy, alkylamino, dialkylamino, or(carboxy)alkoxy.
 14. A compound according to claim 1 of Formula II

and pharmaceutically acceptable salts thereof, wherein X′ is OR₁, SR₁,NHR₁, or NR₁R₂, wherein R₁ and R₂ are independently selected from C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, benzyl, C₃-C₇ cycloalkyl, andphenyl, wherein: the alkyl, alkenyl, alkynyl, benzyl, and phenyl groupsare optionally substituted with from 1 to 5 substituents independentlyselected from halo, NHR₃, CF₃, C₁-C₆ alkyl, OR₄, CO₂R₃, NO₂, and SR₃,wherein R₃ and R₄ are independently H or C₁-C₆ alkyl; R is OH, O—C₁-C₄alkyl, or halo; Y is NR₆ or O, wherein R₆ is H or C₁-C₆ alkyl; Z is2-indolyl, or 3-indolyl, 2-benzimidazolyl, 2-benzoxazolyl, C(O)N(O)Ph,or N(O)C(O)Ph, which are optionally substituted with from 1 to 4substituents independently selected from C₁-C₆ alkyl, fluoro, chloro,bromo, iodo, nitro, NHR₇, NR₇R₈, and OR₇, wherein R₇ and R₈ areindependently H or C₁-C₆ alkyl; and R₅ is H, C₁-C₆ alkyl, or benzyl,optionally substituted with R₁, wherein R₁ is as defined above, or is apharmaceutically acceptable cation.
 15. A compound selected from thegroup consisting of: Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,dodecyl ester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,octyl ester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-2-(dimethylamino)ethylester, monohydrochloride; Acetic acid,[[[[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-amino]carbonyl]oxy]-,phenylmethyl ester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,butyl ester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,2-methylpropyl ester; Urea,N-(3,5-dichlorophenyl)-]-N′-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-;Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,ethyl ester; Carbamic acid,[[[5-(1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-, ethyl ester;Urea,N-(4-chlorophenyl)-N′-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-;Urea,N-[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]-N′-(4-methylphenyl)-;Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)2-methoxyphenyl]amino]sulfonyl]-methylester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-heptylester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-pentylester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-(2E)-3-phenyl-2-propenylester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-2-(1-methylethoxy)ethylester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,phenylmethyl ester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-2-phenylethylester; Acetic acid,[[[[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]-amino]sulfonyl]amino]carbonyl]oxy]-,methyl ester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-3-hydroxypropylester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,2-ethoxyethyl ester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-3(phenylmethoxy)propylester; Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-hexylester; and Carbamic acid,[[[5-(5,6-difluoro-1H-indol-2-yl)-2-methoxyphenyl]amino]sulfonyl]-,1,1-dimethylethyl ester.
 16. A pharmaceutical composition, comprising atherapeutically effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt thereof, in admixture with apharmaceutically acceptable carrier, diluent, or excipient.